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Elicitors, Effectors,
and R Genes: The New
Paradigm and a Lifetime
Annu. Rev. Phytopathol. 2007.45:399-436. Downloaded from arjournals.annualreviews.org
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Supply of Questions
Andrew F. Bent1 and David Mackey2
1
Department of Plant Pathology, University of Wisconsin–Madison, Madison,
Wisconsin 53706; email: afb@plantpath.wisc.edu
2
Department of Horticulture and Crop Science, The Ohio State University,
Columbus, Ohio 43210

Annu. Rev. Phytopathol. 2007. 45:399–436 Key Words
The Annual Review of Phytopathology is online at PAMP, MAMP, avirulence, gene-for-gene, leucine-rich repeat
phyto.annualreviews.org

This article’s doi: Abstract
10.1146/annurev.phyto.45.062806.094427
The plant basal immune system can detect broadly present microbe-
Copyright  c 2007 by Annual Reviews. associated molecular patterns (MAMPs, also called PAMPs) and in-
All rights reserved
duce defenses, but adapted microbes express a suite of effector pro-
0066-4286/07/0908-0399$20.00 teins that often act to suppress these defenses. Plants have evolved
other receptors (R proteins) that detect these pathogen effectors and
activate strong defenses. Pathogens can subsequently alter or delete
their recognized effectors to avoid defense elicitation, at risk of a fit-
ness cost associated with loss of those effectors. Significant research
progress is revealing, among other things, mechanisms of MAMP
perception, the host defense processes and specific host proteins that
pathogen effectors target, the mechanisms of R protein activation,
and the ways in which pathogen effector suites and R genes evolve.
These findings carry practical ramifications for resistance durability
and for future resistance engineering. The present review uses nu-
merous questions to help clarify what we know and to identify areas
that are ripe for further investigation.

399

ANRV319-PY45-17 ARI 22 June 2007 19:14

INTRODUCTION part model has been nicknamed, only par-
tially in jest, the new “Central Dogma” of
In the middle of the previous century,
plant pathology. This important model de-
NB: nucleotide landmark findings were made regarding gene-
binding scribes an evolutionary process. Plants, in ad-
for-gene plant disease resistance, infection-
dition to their preformed physical and chemi-
LRR: leucine-rich induced synthesis of antimicrobial phytoalex-
repeat cal barriers, first have an immune system that
ins and PR proteins, and pathogen virulence
can detect generic conserved components of
through production of toxins and hydrolytic
most microorganisms. In part two, certain
enzymes (108). Subsequently, when scientists
microbes become adapted pathogens of cer-
met 10–20 years ago to discuss pathogen
tain plant species by evolving virulence fac-
virulence and plant disease resistance mech-
tors that actively suppress parts of the general
anisms, key questions emerged. These
defense response in these hosts. In part three,
included:
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adapted pathogens are repelled when the host
by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. For personal use only.

Do plants have a different R gene for almost
species evolves specific R genes, whose prod-
every strain of every potential pathogen? If
ucts indirectly detect the defense-suppressing
not, what do they have that makes them re-
virulence factors by detecting their effect on
sistant to so many potential pathogens?
specific host proteins. Finally, the pathogen
evolves further and escapes detection by the R
Why do pathogens have avr genes if, un-
gene product by eliminating the detected vir-
like toxins or hydrolytic enzymes, these avr
ulence factor or suppressing the defenses in-
genes just hurt the pathogen’s chances for
duced by R gene products. Figure 1 illustrates
success?
this model. Similar models have also been de-
How relevant are defense activation by scribed elsewhere (31, 44, 88).
chitin or plant cell wall fragments, or de- The model of Figure 1 is an important
fense responses such as phytoalexin or PR and successful crystallization of many find-
(pathogenesis-related) protein production? ings. In this review we describe a subset of the
Because, in contrast to gene-for-gene sys- recent discoveries about virulence and resis-
tems, these have not been shown to play a tance that expand or solidify the “take-home”
causal role in disease resistance. generalizations of this new model. However,
How does the “lock-and-key” interaction this new paradigm has brought into focus
between R and avr gene products work? a new set of questions, exceptions, and un-
explained findings. The questions from 10–
On the heels of impressive research 20 years ago that have been answered in
progress, a revised four-part model for plant part are being revisited, and the new Cen-
disease resistance has emerged that provides tral Dogma is already undergoing revision.
some answers to these questions, This four- We present a useful collection of questions
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→
Figure 1
Model for the evolution of bacterial resistance in plants. (a) Recognition of pathogen-associated
molecular patterns (such as bacterial flagellin) by extracellular receptor-like kinases (RLKs) promptly
triggers basal immunity, which includes signaling through MAP kinase cascades and transcriptional
reprogramming mediated by plant WRKY transcription factors. (b) Pathogenic bacteria use the type III
secretion system to deliver multiple effector proteins that target host proteins and suppress basal immune
responses, allowing significant accumulation of bacteria in the plant apoplast. (c) Plant resistance proteins
(R gene products, such as a TIR-NB-LRR protein) recognize effector activity and restore resistance
through strong effector-triggered immune responses. (d ) Pathogen avoids R gene-mediated defenses by
modifying or eliminating the effector(s) that triggers those defenses. This state resembles that shown in
(b) except the pathogen has had to alter or lose an effector protein, or deploy an additional effector
protein. Similar models can be drawn for other plant pathogens. Figure redrawn from (31).

400 Bent · Mackey

ANRV319-PY45-17 ARI 22 June 2007 19:14

a Pathogen
RLKs

PAMP recognition
triggers immunity
Plant cell
MAPKKK

Resistance MAPK

WRKY PAMP-
triggered
immune
Nucleus responses
Annu. Rev. Phytopathol. 2007.45:399-436. Downloaded from arjournals.annualreviews.org

b
by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. For personal use only.

RLKs

TTSS effectors
suppress immunity

MAPKKK Effector ?

Effector
Susceptibility MAPK
Effector
PAMP-
triggered
immune
responses

c
RLKs
R proteins recognize
effector activities

MAPKKK Effector ?

Effector
Resistance MAPK
TIR-NB-LRR Effector
WRKY
Effector-
triggered
Nucleus immune
responses

d
RLKs

Effector recognized
by R protein is
lost or modified
Kinase
MAPKKK Effector ?
Nucleotide-binding
Toll-interleukin 1 receptor
Susceptibility MAPK
(but less virulence) TIR-NB-LRR Effector Leucine-rich repeats
WRKY
Effector-
triggered
Nucleus immune
responses

www.annualreviews.org • Elicitors, Effectors, and R Genes 401

ANRV319-PY45-17 ARI 22 June 2007 19:14

and briefly summarize alternative models, tive immunity. This idea derives in part from
modified terminology, and/or opportunities the observation that basal defenses are only
for important future research. Areas with po- partially effective at restricting pathogens. It
MAMP:
microbe-associated tential for future disease resistance engineer- also derives from the concept that basal de-
molecular pattern ing are also highlighted. fenses are relatively static, i.e., capable of
PAMP: evolving to recognize novel infection threats
pathogen-associated only over many generations, whereas plant
molecular pattern MAMPS, MAMP RECEPTORS, disease resistance mediated by R genes is
AND BASAL IMMUNITY (AND sometimes portrayed as the plant adaptive im-
NOMENCLATURE!) mune system. Each of these ideas requires
The first panel of Figure 1 alludes to a system clarification and revision, especially when the
often referred to as the basal immune system, goal is to accurately describe plant immune
Annu. Rev. Phytopathol. 2007.45:399-436. Downloaded from arjournals.annualreviews.org

which induces responses referred to as basal systems. It is important to disentangle the ter-
by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. For personal use only.

defenses. It was discovered over 30 years ago minology and paradigms used to describe
(4, 22, 67) that plant defense responses can plants from those borrowed from animal re-
be activated by relatively generic signals of search with only partial success. For exam-
pathogen presence, which were often called ple, some R genes compose a more rapidly
elicitors [for recent reviews see (31, 88, 130, evolving component of the plant basal im-
196)]. mune system than MAMP receptors, but they
One key concept surrounding basal im- are not an “adaptive immune system” in that
mune systems is that they recognize cer- they do not regularly undergo useful diversi-
tain broadly conserved molecules associ- fication and selection in the somatic cells of
ated with a wide range of pathogens. The individuals.
term pathogen-associated molecular pattern Most readers will already be familiar with
(PAMP) was developed by researchers of the concept of R (resistance) and Avr (avir-
the mammalian innate immune system to ulence) genes. Gene-for-gene disease resis-
describe this type of defense-activating tance is economically important—it is used
compound. The term MAMP (for microbe- in numerous crops to confer highly effective
associated molecular pattern) is gaining fa- disease resistance (108, 148, 158). Plants have
vor because nonpathogenic microorganisms many R genes and pathogens have many Avr
also possess PAMPs. Well-developed exam- genes. Simply described, disease resistance is
ples of MAMPs that are detected by plants observed if the product of any particular R
include bacterial flagellins, lipopolysaccha- gene has recognition specificity for a com-
rides or elongation factor-Tu, fungal chitin, pound produced due to a particular pathogen
or oomycete Pep-13 or heptaglucosides (87, Avr gene. We will see below that many
196). A related concept from both plant and Avr gene products contribute to pathogen
animal research is that the genes for host virulence.
MAMP receptors are relatively stable and her-
itable, allowing the capacity for early detec-
tion of microbial infections to be preserved What Is the Difference between a
and passed from generation to generation MAMP and an Avr Gene Product?
(81, 130). This is in contrast to mammalian The difference is becoming less clearly de-
adaptive immune systems that “reinvent the fined. Formally, the latter are named aviru-
wheel” of recognition specificity in each new lence genes because they cause avirulence in
individual. A third concept is the perception the presence of R genes. In the absence of a
that basal immunity has a relatively primitive cognate R gene, Avr genes often make a quan-
and inferior immune capacity relative to adap- titative contribution to virulence yet are not

402 Bent · Mackey

Absence of FLS2 makes the what plant tissues. plants more susceptible to this pathogen. These traditional definitions turned on. showed increased suscep- raises a challenging question: In the biolog. Purified MAMPs triggered pathogen can build appreciable interior pop- stomate closure and bacteria did as well. to be an Avr gene). sis plants lacking the flagellin receptor FLS2. a threshold level of are not defining features (think. A plant normally mutation of the host receptor (198). for example. and in tional FLS2. 2007. smaller or pri. bial species. MAMP must be present before the response of an essential viral replicase that is shown is activated. recent study in which stomate closure was dis. This review is or. Note that DC3000 infested with living microorganisms. defenses. applied to plants by humans. but ulations and more effectively counter host only when they swarmed around the stom. many MAMPs to pathogen viability. the apoplast (198). as the first few Further tissue specificity was suggested by a pathogen individuals are entering the plant. Downloaded from arjournals. The first ex- microorganisms carry these defense-eliciting periments to convincingly show a contribu- molecules yet are not pathogens. Phytopathol.annualreviews. For personal use only. Effectors. ANRV319-PY45-17 ARI 22 June 2007 19:14 essential for pathogen viability. whereas significantly improve plant disease resis- MAMPs are defense elicitors that are evolu. for example. including many nonpathogenic a transmembrane protein with extracellular microorganisms that it would seemingly be leucine-rich repeats (LRR) and an intracellu- counter-productive to defend against. tomato strain DC3000. The gered? One can postulate that microorgan. and intact still have utility. As noted above. but exceptions are now known plants may even have been shown to allow Annu. itors and their counterparts in the host are periments the compounds usually have been being actively considered. and R Genes 403 . FLS2-activated responses tions are usually less potent at inducing PR are known to arise quickly. is required to allow sufficient defense activa- covered as a plant defense against bacterial tion (including stomatal closure) before the infections (117). lence due to the central contribution of most curacy to our thinking. www. One might pursue experiments in which siders some alternatives. in doses and/or ganized around the traditional definitions. in these ex- by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. This lar protein kinase. disease resistance took a different approach. not when they were introduced directly into marily external/epiphytic microbial popula.org and new classifications for these defense elic. tibility to infection by Pseudomonas syringae ically realistic setting of an intact plant pv. However. (56). how does cause disease on plants that carry a func- much MAMP needs to be present. forming a core component of numerous examples where purified pathogen- the microorganism that cannot be sacrificed derived compounds caused elevated plant dis- or even altered much without seriously im. ease resistance. Some Avr proteins can There is a more basic question to ask: Has evolve substantially or may be entirely absent MAMP perception ever been shown to from certain strains of a pathogen. but locations that may not mimic natural infec- also highlights their shortcomings and con. Perhaps early detection. tect their MAMPs (12). Rev. or are not tion of MAMP perception to whole-plant pathogens of many of the hosts that can de. expression of a MAMP is knocked out in The term MAMP (microbe-associated the pathogen. within minutes gene expression and other active defenses. for defenses to be trig. Arabidop- grows in the presence of hundreds of micro.45:399-436. tance? The plant pathology literature carries tionarily stable. PR proteins expressed.org • Elicitors. although these atal opening. Defense pathways have been pairing viability. less pathogen growth. tions. Apparently. but these strains will gener- molecular pattern) is increasingly used in ally show reduced rather than enhanced viru- place of PAMP because it lends greater ac.annualreviews. contribution of flagellin perception to re- isms must reach a critical mass in the plant sistance was detected only when the bacte- interior before the basal immune system is ria were sprayed onto the leaf exterior and strongly activated.

pathogens carry versions of a MAMP that sis or Nicotiana benthamiana (34. an abundant protein that is a highly conserved component of the pro. fectors to suppress basal defenses is host spe- cation and knock-out of MAMP receptors are cific. EFR1 controls responsiveness to amiRNA: artificial bacterial EF-Tu. For personal use only. 151). ception systems of plants (FLS2) and ani- The terminology shift from PAMP to mals (TLR5) both recognize flagellin domains MAMP highlights a key question: Across that are highly conserved.. EFR1 is a transmembrane difficult to detect. How often would po. The ability of ef- Nicotiana benthamiana model system. species have been identified that carry suffi- tential pathogens actually be pathogens on a ciently different amino acid sequences in these given host if not for MAMP-activated basal flagellin domains to escape detection by the immunity? This is another question for which host (9. tors that suppress the basal immune system. flagellin protein are constrained by require- how widely is it the case that poten. These domains of the range of plant-microbe associations. Annu.and intermolecular tial pathogens are nonpathogens primar. indeed effective against potential pathogens pressive research progress in the less tractable that fail to suppress them. pathogens have evolved proaches to knock down gene expression in other defense-minimizing strategies. contacts to form the functional flagellin poly- ily because of basal defenses activated via mers that compose the bulk of a flagellum MAMP detection? Another way of phras. pathogens deploy effec- Agrobacterium-delivered T-DNA was signifi. are not detected by their host. This type of applied to address this question. ities (see below). disrupting variability is often observed among Avr genes specific MAMP receptors. silencing LRR-kinase.org cantly improved in plants lacking EFR1. especially as one moves a microorganism to be a “pathogen” only on beyond Arabidopsis to other plants. bidopsis researchers may now be able to use devoted to suppressing basal defenses can be the Agrobacterium-mediated transient gene construed as evidence that basal defenses are expression method. ANRV319-PY45-17 ARI 22 June 2007 19:14 The MAMP receptor knock-out approach expresses multiple MAMPs that engage mul- was subsequently used to show an apparent tiple MAMP receptors. 71. which likely contributes to the ability of not simple processes. Like FLS2. The plethora of pathogen effectors that are by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. Variability in the con- we still need answers. but they a subset of hosts. and mutation TILLING offer ap. (e. Some plants of economic interest. Downloaded from arjournals. but if a pathogen rather than MAMPs. and the difficulty is served/recognized flagellin domain has even not solely due to the need for research on a been detected among different strains within wide range of pathosystems. Increasingly More MAMPs as They sicaceae. campestris (164). may be the best approaches to demonstrate the relevance of any particular MAMP recep- tor in plant disease resistance.g. but there is practical relevance to Reach Higher Population Levels? this finding: transient in planta expression of As discussed below. Phytopathol. 164). How Can Successful Pathogens micro-RNAs tein synthesis apparatus. Yet a small number of pathogen ing this question is.45:399-436. 137. Virus-induced How Stable Are MAMPs? gene silencing (VIGS). Rev. the contribution of contribution to resistance by Arabidopsis EFR1 any single receptor may be quantitative and VIGS: virus-induced gene (197). 56. Xanthomonas expression-knock-down strategies might be campestris pv. 9). It is logi- but the candidate receptor gene must first be cal that the best-characterized flagellin per- identified. beyond Arabidop. Ara. 2007. which has fostered im. MAMPs are generally 404 Bent · Mackey . Mutational or a single species and pathovar. Identifi. ments for precise intra. 142. artificial micro-RNAs In addition to defense-suppressing capac- (amiRNA).annualreviews. Detection of EF-Tu Grow in the Host Despite Presenting has been found only in plants of the Bras.

198). 153. portion of FLS2 was recently shown to di- As additional defense-avoiding strategies. Effectors. 137. In the other example. it has been suggested that it is a departure from the “guard” mecha- some bacteria shed their flagella upon enter. Constitutive activation of this transmembrane proteins with an extracellular system caused elevated resistance to Pythium LRR and an intracellular protein kinase (62. both encode pression (194). The PEPR1 system may kinase found to be involved in plant defense act to minimize opportunistic infection of was an R gene product. 121. crobial compounds or osmotic stress. The defenses fixing rhizobium bacteria (60. FLS2 and EFR1 respond to entirely dif- contribute to pathogen virulence or to the in. molecules or as protectants against antimi. 168). in Annu.org ing the host. the extracellular adaptable mindset. plant defense responses (197). but are also that the eliciting signals for these receptors possible protectants that enhance virulence are plant-derived compounds. Downloaded from arjournals. Like? methyl jasmonate. (95. ANRV319-PY45-17 ARI 22 June 2007 19:14 portrayed as broadly conserved and essential tein (41. bivory. 125.g. are not known.. For personal use only. and other wounded tissues by amplifying innate immune plant R proteins also have this structure (159). detail. respectively. and the systemin receptor of Solanaceae is an LRR-kinase (150). tein upon herbivore attack. Systemins are by excluding plant antimicrobial compounds peptides produced from a prosystemin pro- (49). revealing a number of interesting fea- clude not only action as low MW signaling tures [e. making it reasonable to antici- proteins that are stable targets for recogni.45:399-436. tween plants and animals has frequently been www. with for at least two of these signals are also trans- somewhat variable structures and hence vari. A separate LRR receptor protein has organisms furnishes exceptions to most rules. Xa21 of rice. But the adaptability of natural future. and this concept and MAMP receptors will be uncovered in the remains valid. and it has been demonstrated which some R proteins do not directly bind by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. or ethylene. nisms described at greater length below. pathogen effectors. 117. Figure 2 provides more detail regarding pathogen for which effective plant R genes the structure of LRR domains. For example. tide derived from this protein directly binds to but a trend has been established.annualreviews. been identified that detects ethylene-inducing and the MAMP definition requires an equally xylanase (144).org • Elicitors. a type of broad host-range fungal 197). This direct bind- least some of their MAMPs when they infect ing is in keeping with past predictions but a host. pate that further overlap between R proteins tion by host immune systems. 63). 163)]. membrane LRR-kinases. that some flagellin-knock-out bacteria can re. ferent MAMPs yet both activate very similar fectivity of plant symbionts such as nitrogen. responses. rectly bind a peptide that matches the elicit- some microorganisms may shed or mask at ing flagellin sequence (30). irregulare. It is also intriguing able defense-eliciting activities.annualreviews. Importantly. 119. Bac. FLS2 and and activates the PEPR1 LRR-kinase. the Arabidopsis receptors for bacterial in turn activates defense-associated gene ex- flagellin and EF-Tu. which EFR1. and a pep- There are very few answers to this question. Proposed downstream of FLS2 have been studied in molecular roles for exopolysaccharides in. and R Genes 405 . but also Beyond MAMP detection. the Arabidopsis What Do MAMP Receptors Look PROPEP1 gene is inducible by wounding. Rev. Exopolysaccharides teins. but rather detect them in- tain virulence if introduced directly onto the directly via their perturbation of host pro- host (50. The first LRR. plants carry sys- the masking of bacterial epitopes that might tems that allow detection of wounding or her- otherwise trigger host defense reactions. and it is intriguing that the receptors terial lipopolysaccharides are MAMPs. 140. 2007. Phytopathol. In the appropriate experimental context FLS2 The similarity of MAMP receptors be- itself functions in ways that resemble an R pro. 126.

temin receptor of tomato has the identi- are both receptors with extracellular LRRs cal amino acid sequence as the Arabidopsis that perceive flagellin and activate innate BRI1 receptor for brassinolide hormone. FLS2 and human TLR5. c. noted. Arabidopsis ERECTA is a trans- independently. Some transmem- An intriguing aspect of some MAMP re.org by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. the two Drosophila. Although the two proteins arose animal (134). brane LRR-kinases are known to homod- ceptors is their multifunctionality. yellow and gold highlighting). (c) A single LRR (transverse section through the structure in b). leaving the more variable “x” residues exposed on the protein surface.45:399-436. (a) Consensus amino-acid motif for a plant extracellular LRR. many R protein LRR domains carry degenerate (nonconsensus) subsegments that will adopt other 3D shapes. Figures redrawn from (45. In immune responses (12). However. It is not yet clear how this and human interleukin receptors. imerize but also to require heteromeric 406 Bent · Mackey . Other LRR types have slightly different structures. multifunctionality arises. 107). these and other mechanistic membrane LRR-kinase that controls devel- parallels between the immune systems of opmental traits such as inflorescence config- plants and animals remain a fascinating area uration but also mediates resistance against for further research (12). and d ) are primary candidates for determining pathogen specificity. for example. the Toll receptor controls em- proteins recognize different flagellin domains bryonic development and then later con- and the LRRs do not exhibit common trols innate immunity responses in the same derivation. polygalacturonase inhibiting protein (1OGQ) of Phaseolus vulgaris. Phytopathol. 46). 2007. For personal use only. (d ) Close-up of the β-strand/β-turn region. Downloaded from arjournals.annualreviews. The sys. asterisks in a). A typical LRR domain carries 21–25 amino acids per repeat and forms a large helix of multiple such repeats. Rev. The leucines and other hydrophobic residues that occur at regular intervals are driven to the protein interior in an aqueous environment (red highlight in c. d Figure 2 Leucine-rich repeat (LRR) structure. ANRV319-PY45-17 ARI 22 June 2007 19:14 a * * * * * * * 24 LRR motif: 1 xxLxLxxNxLt/sGxIPxxLxxLxxL * * * ** 1 b c Concave face 24 β-strand/β-turn region Convex face 10 7 Annu. The entire LRR domain is curved and the concave surface carries a β-sheet (β-strand/β-turn region. (b) An LRR protein. where 5 solvent exposed residues per repeat ( yellow highlighted in a. some Ralstonia solanacearum (vascular wilt bacteria) plant R gene products carry domains with and Plectosphaerella cucumerina (necrotrophic similarity to the intracellular domains of Toll fungi) (61. For example.

such as those perceived by PEPR1 receptors.. bound compounds might escape detection inducing activity—was demonstrated over due to small changes in structure. But (4). or established (46). it may de. long as it causes a host compound to be al- turonides of intermediate chain lengths (i. PGIP may tion surface that is well suited to interact with also cause more defense-eliciting oligogalac- multiple ligands. PGIP is the first plant nents that are available to the receptor-kinase LRR protein for which a crystal structure was Annu. tween MIMPS (or WHIMPs) as opposed PROPEP1. rice. and poplar genomes show that indi.g. by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. making detection of this involves plant LRR proteins.annualreviews. charides to be present. Directly host-derived compounds that have defense. of pathogen polygalacturonases. Rev. We return to these sub- polygalacturonase-inhibiting protein (PGIP) jects at multiple junctures below. were shown in many of defense-suppressing pathogens and herbi- studies to induce defense-associated responses vores might cause production of the same (e. and polygalacturonases. Phytopathol.org in different cell types. What Should We Call the vidual plants carry a few hundred different Defense-Eliciting Molecular LRR-kinase proteins. Pathogen-Derived Compounds? ther set of predicted extracellular LRR pro. and a fur. a pathogen will be detected regardless of degrading enzymes such as xylanases. Multifunctionality may indicate that ficity for certain fungal polygalacturonases the protein is a coreceptor and not the pri.. 178). subcellular locations. Furthermore. an additional few hun. they re. tered into a detectable MIMP or WHIMP 5–15 hexose units). 157. onase degradation of host cell walls. By delay- sibly depending on the coreceptors present in ing rather than entirely blocking the activity the complex. In a striking example that again MIMP or WHIMP.org • Elicitors. derived from plant cell (183). This protein enhances plant disease re- mary ligand receptor. (45).e. pectate the structure of the molecules it produces as lyases. developmental stages.45:399-436. In the case of or effectors. it has more re. pos.. For personal use only. patterns) (112). sistance. Downloaded from arjournals. Effectors. main a likely target group from which to the accurate acronym would be WHIMPs identify additional MAMP-receptors and R (112). There are very important evolu- proteins. 2007. Thus. and some R genes—that pathogen to MAMPs and those Avr proteins that are action on the host can cause release of directly bound by host receptors. www. The proposal has been made to call these com- teins with a transmembrane C terminus and pounds MIMPs (microbe-induced molecular little or no cytoplasmic domain (58. Alternatively. as is described below development and other processes but many when indirect recognition of Avr/virulence ef- of these receptors may recognize MAMPs fector proteins is discussed. Many pathogens secrete plant cell wall. MIMPs compose a very sig- Some of these proteins participate in plant nificant class of elicitors. many different species wall polysaccharides. and its effectiveness may be due rive from a capacity to directly bind more than only in part to limitation of polygalactur- one type of ligand with high specificity. ANRV319-PY45-17 ARI 22 June 2007 19:14 “coreceptor” proteins for function (e. compound a broadly effective element of the cently been shown that pea plants secrete a plant immune system. 16. 40. 68). The completely sequenced Arabidopsis. Multifunctionality also may turonide intermediates and fewer monosac- derive from the downstream signaling compo.g. either exclusively or as one wound/herbivory-induced molecular patterns of their multiple ligands. and R Genes 407 . thereby 30 years ago by Albersheim and colleagues conferring advantage to the pathogen. Patterns that are Produced from dred predicted transmembrane kinases with Host Compounds Rather than from non-LRR extracellular domains. 189). LRRs produce a broad interac.annualreviews. Oligogalac. that is essentially a large LRR with speci- 91. tionary implications to the distinction be- The paradigm noted above for systemin.

In other words. transgenic introduction of novel DISEASE CONTROL? MAMP receptors may in the future allow re- Many farmers can name useful R genes but few searchers to engineer plants with enhanced have heard of PAMP receptors or MAMP re. The growing assumption is that there are agriculturally important plant families. as targets for engineering. expres. resistance of a plant. proaches to the enhancement of plant disease sistance. and should help DUAL FUNCTIONS IN to identify MAMP receptors (or other traits) VIRULENCE AND AVIRULENCE that make the most significant contribu. and to what cipient. There are also many MAMP-independent ap- tative and multigenically controlled basal re. any efforts to improve upon the MAMP detection systems of plants must account for a key observation: MAMP- Which MAMPs and MAMP activated defenses are frequently blocked by Receptors Make Significant pathogens. fector biology. Many other types of traits also con. As an alternative. MIMPs or WHIMPs may also serve extent can an effective basal immune re.45:399-436. Contributions to Resistance? Forward genetic screens are needed to di- rect attention toward phenotypically signifi. Defense-suppressing effectors appear in part tions to quantitative resistance. be pathosystem spe. suggesting that at least some MAMP ins and effector proteins. but MAMPs and MAMP receptors tribute quantitatively to resistance (such as deserve consideration. Of course. we focus ods. Downloaded from arjournals. to enhance the defenses they activate. avirulence function. 408 Bent · Mackey . The answer two of the four-part model described above will. 2007. For personal use only. fense receptor. Phytopathol. MAMP ing question: How many different MAMPs receptors might be moved across species to does a single host typically detect from expand the basal immune system of the re- a single potential pathogen. resistance. the intended virulence func- sion of genes that encode LRR-kinases might tion is often overshadowed by a dominant be knocked-down by reverse-genetic meth. For example. can be defined as research should focus on major diseases of pathogen-derived molecules intended to pro- major crops. Native receptors might be ceptors. or- sponse be activated by a single type of thologs of the Arabidopsis WHIMP precur- Annu. such as tox- cific. ANRV319-PY45-17 ARI 22 June 2007 19:14 HOW DOES MAMP BIOLOGY Regardless of their present contribution to RELATE TO PRACTICAL resistance. MAMPs that are rel- leaf canopy architecture and proclivity to re. attractive targets for detection by immune systems. PATHOGEN EFFECTORS HAVE cant molecular mechanisms. Are those priorities misplaced? Any “souped up” to recognize other MAMPs or answer will relate in part to the follow.org MAMP as opposed to an array of MAMPs? sor PROPEP1 are already present in many by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. development outside of the host. Mutational keeping” function in microbial growth and studies may be needed to identify nonpoly.annualreviews. Effectors. atively constant (immutable) are particularly tain leaf surface moisture) (128). followed by testing with pathogens or on the impressive progress in deciphering ef- elicitors. Rev. in many cases. as one aspect of quanti. when an effector is recognized by a host de- tors to resistance. and in Figure 1. morphic traits that are significant contribu. Resistance can be dissected mote pathogen virulence by interacting with by QTL analysis to identify the candidate the host. effectors are viru- genes at primary contributing loci. but this lence factors that usually do not have a “house- only identifies polymorphic traits. disease resistance. However. In this section. and multiple MAMP receptors that each make this type of compound may offer substantial additive contributions to the overall disease opportunities for crop improvement (194).

Two major breakthroughs led to an ap- preciation that bacterial effectors are active inside the cells of the host: effector pro- teins expressed directly inside host cells (e. as is also fundamentally related. and is known to be central to secretion system R gene-mediated activity induces defenses the virulence of numerous bacterial pathogens that prevent virulence (108). 149). This raised the question: (6). isogenic pairs of vir- tors into cells of the host.org where they contribute to virulence (6. by screening bacterial genomic Pathogen Have? libraries for genes that convert virulent bac- Individual pathogens deliver dozens of effec- teria to avirulence (162. 28). How Do R Proteins Recognize the via transiently or stably delivered DNA) fre. oomycetes are likely to secrete many more ef- The hrp mutations disrupted the ability of fectors than do bacteria (89. for example. Rev. and includes the death which oomycete proteins will be secreted. 99). these results widely assumed that they must contribute in led to the hypothesis and subsequent confir- some way to pathogen fitness. pathogens can deliver a that they also provide functions essential for potpourri of effectors into cells of the host. by virulence (72. response basis of their avirulence activity. it was of plants and animals. Together. Downloaded from arjournals.. and R Genes 409 . Effector genes were first isolated as avir. 64). These were pilus is now called the type-three secretion appropriately called Avr genes since their TTSS: type-three system (TTSS). 57. as they by contributing to virulence on a susceptible are now called.annualreviews. 179).45:399-436.org • Elicitors. Bacteria deliver ulent and avirulent pathogen strains remain many type III effectors beyond those known a powerful tool for many types of studies). Earlier views of this and related subjects from the bacteria into the cytosol of plant cells can be very stimulating to read [see (52. 93. As was discussed www. 187)]. Thus. Today. These findings paral- seen in effectors from malaria parasites of hu- leled work on viral avr genes demonstrating mans (21. How Many Effectors Does a ulence genes. Recent work has demonstrated helped provide answers (6. For personal use only. 2007. Based on a motif that predicts mediated resistance. Many of phytopathogenic bacteria to cause the HR on the effectors that are secreted into the extra- resistant hosts and pathogenesis on suscepti- cellular space by oomycete pathogens carry an ble hosts. 104). Effectors. ANRV319-PY45-17 ARI 22 June 2007 19:14 Why Are avr Genes Maintained by the pathogen (6. The number of type III effectors that bac- How do intracellular R proteins perceive teria introduce into hosts is large. to be Avr proteins. However. The hrp. effectors is well established. individual the presence of extracellular pathogens? strains express anywhere from 20 to nearly The identification of bacterial hrp mutants 100 (38. a variety of mechanisms. and newly identified type A powerful clue to effector biology emerged III effectors currently are called Hop genes when the first R genes were cloned and found (for hrp outer proteins.g. providing evidence that the aviru- RXLR amino acid motif that targets the pro- lence and virulence activities of effectors are teins for endocytosis by host cells. 103). and some of the proteins Pathogens? encoded by hrp genes form a pilus capable of secreting bacterially encoded proteins into Many effectors were first identified on the HR: hypersensitive the extracellular milieu (6. note that some of to encode cytoplasmically localized proteins these may have Avr-activity in some hosts) (discussed below). Annu.annualreviews. can be delivered via the TTSS host. the of plant cells local to the site of infection (75). Presence of Effectors? quently possessed avirulence activity similar This is one of the most prominent questions to that observed when they are expressed by in plant pathology research. mation that type III effector proteins. Phytopathol. the virulence role of many by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. 85. 89). The hyper- that oomycetes also secrete effectors into both sensitive response (HR) is a robust defense the extracellular space and the inside of host response frequently associated with R gene- cells (89).

ANRV319-PY45-17 ARI 22 June 2007 19:14 above. Rev. 145. There is interesting evi- interact with intracellular effectors. tions: What defense processes are sup- fector contributes to virulence only if recog. 10. Phytopathol. It was proposed that effectors ing the host target to avoid detection. 48. Thus the The evolution of effectors is influenced by main question can be rephrased as two ques- how they are perceived by R proteins.org indirectly (183). see discussion be recognized indirectly [e. If the effector can maintain its interaction with a defense receptor. Exceptions may arise [see for example tion. However. 152. pressed by effectors? What host targets nition by R proteins is avoided. tors that are directly recognized. 154). The most information to date about the viru- rupt the physical interaction with an R pro. 110. effector protein sequence can potentially dis. below]. 84. tion while indirectly recognized effectors are turbed. target. But age (3. target host proteins other than R proteins. So perception of pathogen effec- tors by R proteins occurs in one of two ways: either directly. A key question is whether those changes has come from studies of type III effectors are compatible with the virulence activity of from bacterial pathogens. one different host target and avoid detection tease cleaves a host protein kinase.annualreviews. direct interaction between ef. Downloaded from arjournals. 410 Bent · Mackey . Mutation to are perturbed by effectors? Understand- avoid recognition is a viable option for effec. Changes in mechanistically. The postulated that R proteins recognize effectors effector would generally have to stop perturb- Annu. in many cases.g. this appears to be true in a number of cases and oomycete plant pathogens that apparently [(43. while continuing to impact other targets. However. and the by ceasing to attack the guarded host target cognate R protein (RPS5) detects such cleav. 47. Virulence? Recent work shows that effectors have highly adapted virulence functions. The two types of recognition have im- portant ramifications with respect to the dura- How Do Defense-Suppressing bility of resistance conferred by a particular R Effectors Enhance Pathogen gene. (7. The effector may attack more than provides a straightforward example: This pro. 106)]. 37. it was widely hypothesized that cytosolic R it will escape recognition while maintaining proteins would serve as receptors that directly virulence function.g. An ef. An alternative model came with more rare to evolve forms that escape recogni- formulation of the “guard hypothesis. dence concerning proteins from virus. syringae effector protein AvrPphB (32. that are recognized indirectly it may be much tor detection. 101)]. see below]. The P. these types of R proteins a trend seems to be emerging that directly rec- “guard” the targets of effectors and induce de. MAMPs can be recognized by direct the effector.45:399-436. (13. 111. Indeed. lence activity of pathogen-encoded effectors tein. activity in the context of such mutations. For personal use only. analogous to recognition of PATHOGEN EFFECTORS MAMPs by MAMP-receptors. for effectors fector and R protein does not explain effec. 167). fungus. 2007.” which tion while maintaining virulence activity. 72. have evolved to escape host detection [e. Similarly. ing the host targets is key to understanding. or indirectly PROMOTE VIRULENCE BY via their perturbation of “guarded” host tar. Thus.. how the effectors function. 154)]. ognized effectors often undergo diversifica- fense responses when those targets are per. but the by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. Numerous effectors are now known to either present or deleted [(112). SUPPRESSING HOST DEFENSES gets. virulence contribution of such effectors will and that perturbation of those host targets usually be dependent on perturbing the host is the trigger that leads to R protein activa.. They perturb How Do Effectors Avoid Recognition specific host targets in order to disrupt specific by R Proteins? host processes—often host defenses.

2007. induce numerous (129). fectors suppress MAMP-induced callose de- GEF: guanine clear. it is reasonable to speculate that presses a broad spectrum of transcription in. numerous effectors have now been tion of HopM1 to bacterial virulence. Basal resistance can involve reduced vas- press transcription of a few transcripts in. Unlike classical R proteins. Effectors. Hauck et al. either purified or presented by important virulence target for the bacteria TTSS-deficient bacteria. a previous section (117). and R Genes 411 . reinforcing and antimicrobial components to it is now apparent that at least one MAMP the site of interaction with the pathogen (141). because mu- of MAMP-signaling by numerous bacterial tations that block penetration-resistance can type III effectors. Vesicle traffic and cell wall–based de- defense readouts that reflect the diversity of fenses are also critical for resistance of plants defense responses induced by MAMP re. Numerous ef- time the role of MAMPs in resistance was un. Key to the production of papillae is exchange factor MAMP receptors had not been demonstrated polarized vesicle traffic that delivers cell-wall to have strong roles in resistance. and duced by flagellin (74). By preventing penetration of the fun- induced by MAMP-signaling is as a global gus into the interior of the leaf. One way of viewing the response 105).org • Elicitors. in this case by inactivat- ception makes an obvious contribution to re.annualreviews. cular flow into minor veins of leaves. cating that this protein and presumably the induced defense responses. coding this GEF phenocopies the contribu- Indeed. Notably. vidual gene transcription and global changes The role of MAMPs in penetration-based re- have been used to demonstrate suppression sistance is unknown. FLS2. 95. multiple Arabidopsis proteins. 197. syringae bacteria was noted in by numerous bacterial type III effectors (41. Papillae (also known to use the phytotoxin coronatine (a jasmonic as cell wall appositions) are localized cell wall acid mimic) to overcome this defense by sup- thickenings induced by bacteria and a variety pressing the salicylic acid and abscisic acid www. However. Li et al. callose deposition. these defenses transcriptional response (126. Rev. ANRV319-PY45-17 ARI 22 June 2007 19:14 Inhibition of MAMP-activated signaling of other pathogens. used tran. 74.annualreviews. including a G adapted effectors or are unable to deliver ef. HopM1 in- Annu. bacteria that express non. act upstream of MAP kinase signaling to sup. genesis for which multiple effector biology A landmark 1995 paper (23) anticipated the stories are likely to emerge. 74) regulates vesicle traffic (129). 164. However. can make significant contri. plant (73. indi- directly demonstrated to suppress MAMP. 94. For personal use only. 169). ing a host small G protein that positively sistance are nonhost interactions (41. receptor. Callose has been widely is critical for bacterial virulence. 71. cause powdery mildew susceptibility in non- scriptome analysis to show that AvrPto sup. host plants. Many of the cases in which MAMP per. knock-out of the gene en- cause they fail to inhibit MAMP-signaling. (GEF).org or interaction of a TTSS-mutant with a host duces proteasome-dependent degradation of by NORTH CAROLINA STATE UNIVERSITY on 03/12/08.45:399-436. showed that this process also can be inhibited by defense- a large number of effectors are able to inhibit suppressing effectors (132). Downloaded from arjournals. 73. be. terial effector can inhibit pathogen-induced 198). Thus. syringae is proposed 42. For a long used as a marker for papillae. protein activating guanine exchange factor fectors lack pathogenicity. demonstrated that AvrPto and AvrPtoB that pathogen’s host plant. against nonhost powdery mildew fungi (33. 95. 71. vesicle traffic that it helps to regulate are an MAMPs. postulated position. 95). The role of widely documented fact that MAMPs induce MAMP detection in stomatal closure that re- cell wall–based responses that can be inhibited duces entry of P. 71. Both indi. at least in part. He tors that inhibit cell wall–based defenses in et al. Phytopathol. host-adapted powdery mildews encode effec- duced by TTSS-deficient bacteria (73). flagellin-induced transcription of the NHO1 Plant invasion is a crucial stage of patho- transcript (100). prevent further development of the infection. The example of HopM1 shows how a bac- butions to resistance (41. P. ceptors. 160).

Thus. a number of fun. tors target a multitude of host processes. The gal and oomycete effectors can disarm these host range of a pathogen could be enhanced molecules after they are secreted. or root or shoot epidermal cells ligase (1. Phytopathol. pression of defense in particular hosts. mimics a host E3 ubiquitin vasculature. One such entry routes? This might include the plant effector. 110). Thus type III effectors inhibit the HR other area very ripe for future study (89). Fur- festans are now known to carry a wide suite ther studies of defense suppression will likely of secreted extracellular protease inhibitors reveal more mechanisms of effector function. will reveal the host processes proteases (172–175).org lung and gut epithelia (90). for example. 80). Avr4 was orig. that they target. as even a sin- walls can directly inhibit pathogen growth gle effector that is detected by many potential and/or release defense-eliciting compounds host plants may significantly limit a pathogen’s from the pathogen. Similarly. Some of these are pathogens? Are there MAMP detection generalized inhibitors of PCD whose effects systems that work especially well in other are observed in yeast cells (2. It has long by carrying many effectors with quantitatively been appreciated that plants secrete antimi. overlapping activities. of these pathogens. tions for future research: 412 Bent · Mackey . But pathogens secrete host range (190). We now know that defense-suppressing effec- Oomycete pathogens such as Phytophthora in. press reduced MAMP-sensitivity in their induced by the R protein RPM1 in Arabidopsis epidermal cells? (139). gene-mediated detection of effectors repre- ing fungi (108). effectors may function in a given host. which is required for suites of effectors that are only beginning accumulation and function of RPM1 (13. Pathogen host range is now believed to be fectors block the delivery of antimicrobial strongly influenced by the possession of ap- enzymes or compounds by preventing their propriate effectors that are adapted to sup- secretion. FUTURE CONSIDERATIONS hibits tomato chitinases (181). In a new and more explicit example. it was found that C. these Space constraints allow only brief com- virulence effectors deactivate components of ment on a number of other outstanding ques- a deployed defense response. of biotrophic and hemibiotrophic pathogens. 82). Additionally. 2007. As is often the REGARDING DEFENSE case with bacterial effectors. to be understood. some ef. ANRV319-PY45-17 ARI 22 June 2007 19:14 signaling required to keep the stomata closed. both specific and Different trends are emerging from study general. by a variety of strategies. Rev. Other type III effectors inhibit after the cuticle has been breached. AvrPtoB. Are there MAMP-associated defenses Numerous type III effectors have been shown that reduce stomatal entry of eukaryotic to inhibit HR cell death. Do plants ex. Annu. The HR is a robust defense response Many eukaryotic microorganisms enter the that is associated with resistance to a variety plant by hyphal growth through stom. and which represent an. (EPIs) that inhibit plant-encoded apoplastic and significantly. SUPPRESSING EFFECTORS inally known as an avirulence gene product. Animal the HR induced by a specific R protein. because only a subset of crobial enzymes such as glucanases and chiti. as opposed to sup. fulvum Avr4 in.45:399-436. pressing defense response activation. Yet R nases that degrade the cell walls of invad. This function of AvrRpt2 results from Eukaryotic microorganisms produce large its degradation of RIN4. For personal use only. 95.annualreviews. EPI: extracellular protease inhibitor ata. Downloaded from arjournals. AvrPphC prevents an HR induced topologically exterior surfaces including the by AvrPphF in certain bean cultivars (79). For innate immunity must be down-regulated at example. Degradation of pathogen cell sents a flip side to this strategy. molecules capable of inhibiting antimicrobial compounds (5). AvrRpt2 specifically blocks the HR by NORTH CAROLINA STATE UNIVERSITY on 03/12/08.

and what emerge with important implications for host processes are they targeting? the ecology of mixed infections. the pathogens (8). tical disease control. and for numerous plant fective effectors. Downloaded from arjournals. Do effectors from distinct as part of intracellular NB-LRR proteins that pathogens suppress the same host also carry a nucleotide binding (NB) site and pathways? other conserved domains. 74). Study of broad suite of effectors? R genes should yield knowledge with many  How do defense-suppressing effec. The vast fungi? Commonalities exist in the host majority of R genes encode proteins that carry defense-signaling responses to distinct a leucine-rich repeat (LRR) domain.  Are multiple effectors frequently appear until part three of the four-part model needed to inhibit single host pro.45:399-436.annualreviews. for all diseases. inhibited? An effector that blocks de- fense activation may be more effective than many effectors that block individ. they have long been promi- cesses? Effectors that act strongly when nent in the minds of the plant breeders and artificially overexpressed prior to in. More prominently.  Will effector targets correspond with The shortcomings of R genes are also quantitative trait loci that influence well known (19. ergy of. polymorphism is needed before pathogens (why no R genes against differences in impact can be detected.annualreviews. Rev. 2007. farmers who rely heavily on R genes for prac- fection may not be sufficient in nor. Pathogens then R genes (19) were major landmarks for may need to deliver effectors that each the same reason that study of R genes remains partially suppress the same pathway highly relevant: These genes do an amazing (e. includ-  How many host processes need to be ing opportunistic secondary infections. 53. proteins. They are not available disease resistance? As mentioned pre. Figure 2 www. for example. not on their own cause disease? Such in bacteria and in other pathogens? phenomena have been noted in the syn- Loss of single effectors can cause sub. Potato virus Y. Other examples may tributing to pathogenesis. or in “receptor-like proteins” that fenses induced by other types of have an extracellular LRR and a transmem- pathogens. brane domain but then very little at the intra- tion by microorganisms that would cellular C terminus of the protein. and allow disease causa. outlined above. 88). The initial cloning and mal infections because of lower ex. which is due largely to ically reduces virulence. part 4) (88. Although R genes and their products do not by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. necrotrophs?). Potato virus X and tle effects.org ual defense responses. and the past few years tors contribute to the virulence of have yielded important discoveries. job of stopping plant diseases.g. and/or an unusually diseases their utility is unquestioned. ANRV319-PY45-17 ARI 22 June 2007 19:14  What are the roles of other effectors. Phytopathol.org • Elicitors. Yet some R genes remain cause they carry a few particularly ef. effective for decades. pathogens with different lifestyles. 115). 69. and R Genes 413 . In what way suppression of gene silencing by one of are all of the other effectors con. zoctonia or Botrytis successful be. pathogen populations evolve (see Figure 1. as an extracellu-  Do effectors from one type of lar LRR in transmembrane receptor-kinase pathogen frequently suppress de. 88). R PROTEINS Annu. Earlier findings about R genes have been such as necrotrophic bacteria or rust widely reviewed (19. practical applications. For personal use only. disruption of TTSS dramat. especially for necrotrophic viously. either pathogens. molecular characterization of Avr genes and pression or delayed delivery. Effectors.. 39. R genes  Are important broad host-range are famous for working but then failing as necrotrophic pathogens such as Rhi.

It is now clear that many genes con- mains are also found in many other proteins tribute to R gene phenotypes. Other ple of LRR function comes in the adaptive genes that contribute to an R gene’s phenotype immune system of jawless vertebrates such as may be difficult to detect because they make eels. horizontal re- sistance can be controlled by a single gene of major effect. 2007. Rev. These genes in the biological kingdom. are otherwise essential for plant fitness. see Figure 2) The proteins were shown to make signifi- not only lack conservation.45:399-436. discovered by mutational analysis. through dom drift. As one nice example. sifying sites encode the pathogen-specificity (184)].annualreviews. 414 Bent · Mackey . but many are now known ent binding specificities can evolve. such as barley mlo (27). the basal MAMP-based resistance sys- Themselves. 88). 70. defense. and that their evolu. after a few other aspects butions. 88. Phytopathol. partial/quantitative re- phenotype are not detectably polymorphic sistance is not “useless” or “too hard to work within a plant species. sufficient functional overlap to mask polymor- stead shuffle a small number of progenitor phism at any single locus. but are signifi. ANRV319-PY45-17 ARI 22 June 2007 19:14 describes the appearance of an LRR. by their ilies have shown that LRR domains can be induced expression during infections. which lack T cell receptors and other small contributions to overall disease resis- adaptive immunity elements typical of more tance. home the idea that LRRs are a highly adapt. the stereotypical horizontal resistance tion permits recognition of different pathogen that is only partially effective is in many Avr proteins. (31. a set of E3 lection to maintain function. One particularly interesting exam. 185). a few points deserve brief mention. While Horizontal tems discussed at length above are likely con- Resistance Is Multigenically tributors to nonrace-specific resistance. cant contributions to R gene-mediated de- cantly more diverse than expected from ran. but Controlled? this has never been demonstrated for an agri- Most of the genes required for an R gene’s cultural crop. adopt new function in this part of these R pro. resulting in observ. Turning to horizontal resistance [resis- teins.” it has undergone significant improve- able segregation only of single R loci that ment by plant breeders through large mul- control a particular gene-for-gene resistance tiyear phenotype-based selection programs. tance that is apparently not race specific. This suggests selective pressure to a presently unknown mechanism. with. For personal use only. (minor genes) that each make small contri- tion is taken up below. others. or due under diversifying selection (53. 96). (the β-strand/β-turn region. Sec- Do R Genes Really Act by ond. But. 55. PR protein or phy- LRR-encoding genes to generate a wide ar. and often control may not be polymorphic because they con- ligand binding or protein-protein interaction tribute to the phenotype of many R genes. trait. LRR do. In most to physical interaction of the protein prod- other proteins the key domains are conserved uct with a protein known to be involved in across taxa. ing knowledge of genes that function “down- able structural platform on which very differ.org ray of immune specificities (133). The jawless vertebrates in. at what site do R proteins cases controlled by multiple polymorphic loci recognize pathogens? This important ques. Downloaded from arjournals. domains of R proteins. toalexin biosynthesis genes may represent this Annu. These genes are often Studies of a number of plant R gene fam. But in some R ubiquitin ligases was recently discovered by gene families the predicted solvent-exposed expression profiling and subsequent pheno- residues along the concave face of the LRR typic testing of RNAi-silenced plants (195). stream” of R genes. or (17. This drives class. The prediction has been that the diver. First. fense in Solanaceae and Brassicaceae. as anticipated by Vanderplank and of disease resistance biology are introduced. presumably due to natural se. Third. or because the plant carries genes with recent vertebrates. This review does not cover our grow- by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. But in some instances.

and/or by equal or presence of RPS5 a slight shift in AvrPphB unequal extragenic recombination to gener. 53. R genes are practically impor. with substantial divergence in available. with polymor.org • Elicitors. is also highly diversified (47). should be A recent landmark paper used yeast two. A similar coevo- diseases it is sought because R genes are not lutionary story. for example. shown in other examples (43. shows minimal allelic variability Avr alleles emerge that escape host detection (171). 146). other R genes appear to be under pathogen specificities. tion between R protein and Avr protein seem It is significant that many R genes are likely to emerge. under selection for conservation rather than hybrid assays to show direct interaction be. Rev. 148. direct interaction between tant. Downloaded from arjournals. the R protein. Ellis. For some pathogen interactions (48). described for the Rpp13/Atr13 interaction in- durable) and are overtly being avoided (128. variant Avr proteins. 54. volving Arabidopsis and Hyaloperonospora (7. They represent a flex.annualreviews. They evolve ample was noted above: This NB-LRR R pro- at a faster rate than most genes. structure would not be sufficient to escape ate more/fewer R genes at the locus (39. In the in the resulting products. syringae Avr gene. has been R genes have proven to be unreliable (non. 2007. and R Genes 415 . with specificity The above represents a major new piece for physical interaction matching the R/Avr of the plant pathology dogma. Lawrence. and colleagues have tion on effectors. Given that many other R genes or R gene analogs exist in linked clusters that exhibit substantial al- R PROTEINS DETECT Avr lelic divergence across accessions within the PROTEINS: DIRECT OR Annu. In most cases known to date. 184). 53). ANRV319-PY45-17 ARI 22 June 2007 19:14 and plays a significant economic role in dis. the R proteins that act via an indirect “guard” are an R gene family from flax that occurs mechanism turn out to be conserved. tein activates defense if the Arabidopsis protein phism generated not only by single base mu. It makes sense that such an R pro- yet retain virulence function. As was mentioned above in the sec- Dodds. 158. but horizontal resistance traits are also NB-LRR protein and Avr protein has been important. with new plant tein would be conserved: PBS1 structure is specificities also emerging that detect these unlikely to evolve at an accelerated rate and. accordingly. and AvrP- equal exchange to make longer/shorter LRRs phB specifically cleaves PBS1 (154). rect binding. working with the flax/flax-rust than detecting pathogen Avr proteins by di- pathosystem that was also used by Flor (47. additional examples of direct interac- INDIRECT INTERACTION? by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. Separately. which occurs as a single-copy gene in suggests a gene-for-gene arms race in which Arabidopsis. the pathogen must instead cease The flax rust AvrL567 gene family that allows proteolytic cleavage of the guarded host pro- some of these R genes to confer resistance tein PBS1 if it is to escape detection by RPS5. 158. detection. by intragenic recombination with un. kinase PBS1 is proteolytically cleaved (154). For personal use only. or readily mutable to evolve new the story.45:399-436. Phytopathol. RPS5. some R proteins respond put together a very important body of work to the perturbation of a host protein rather on this topic. Effectors. avrP- by intragenic recombination with equal ex. The L genes. resistance specificity observed in the plant- ease control (128. 48. R gene diversification is only one part of cessions. divergence. The evidence RPS5. nondi- as a tightly linked multigenic cluster of re. 84). The Arabidopsis RPS5 ex- lated NB-LRR-encoding genes. (88. but for others it is used because both the R and Avr gene families. 184). tween the Avr and R proteins.annualreviews. but the dogma www. 98). polymorphic—entirely absent in some ac. encodes a protease that is delivered into change.org species. phB. host cells via type III secretion. 57). tations or small insertion/deletions but also The corresponding P. 148. verging R proteins. conservative rather than divergent selection ible component of the plant immune system.

In light of greater tendency to be forced toward diver. defense signaling (166). but work in additional pathosys. Figure is courtesy of (44). which must proteins. Upon ADP binding the I-2 protein dis- colleagues speculate that R gene defenses played an increased affinity for ADP. Defining domains of NB-LRR proteins edge of how these proteins convert pathogen include not only the nucleotide binding −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ Figure 3 Two related models for NB-LRR R protein activation. fer disease resistance. Avr) affects the LRR domain. these and related findings.org the recognized Avr sites are not readily alter. Takken and col- sification. returns the NBS-LRR protein to its inactive state. Mutant forms of I-2 were generated egories. Presence of the pathogen effector (1) alters the structure of the NBS-LRR protein through direct binding (left) or modification of additional plant proteins (right). In the absence of stimulation. and those that evolve very slowly be functional for NB-LRR proteins to con- and detect Avr perturbation of host pro. (166). Pathogen recogni- tion triggers nucleotide-dependent confor- mational changes that might induce oligomer- FUNCTIONAL MATTERS: HOW ization or otherwise provide a scaffold for DO NB-LRR PROTEINS CARRY activation of downstream signaling compo- OUT THEIR TASKS? nents. (a) Switch function of ATP/ADP binding (165). Dissociation of the pathogen effector and modified effector targets (if present) (3). state of I-2 is the active form that triggers by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. (b) Signaling is activated in a similar way for both direct (left) and indirect (right) modes of pathogen detection (44). ATP binding subsequently triggers a second conformational change in the N-terminal effector domain. and of indirect detection systems that made with Arabidopsis RPS5 (3) and with cer- nevertheless have diversified substantially [as tain animal proteins (176) suggest that this has been suggested for the Cf loci of tomato. Is it accurate to recognition into defense activation. For personal use only. an NBS-LRR protein is in the OFF-state (resting state). Phytopathol. ANRV319-PY45-17 ARI 22 June 2007 19:14 can already be questioned. Takken and colleagues teins? Current findings suggest the validity of have now shown that the I-2 NB-LRR pro- this concept. of R protein. as the pathogens have been purged leagues suggest a functional model in which of effectors that attack the host in ways that the LRRs control the molecular state of the can be recognized by “guard” R proteins (48). 2007. In their landmark paper. and their function suggests been quite stable over time (for example. It can be predicted that there will that are impaired in ATP hydrolysis but not be cases of direct R/Avr interaction that have in ATP binding. tein of tomato binds and hydrolyzes ATP tems is needed to fully substantiate these cat. The presence of an elicitor (effector.rather than the ADP-bound Annu. 416 Bent · Mackey . Figure is courtesy of (165).45:399-436. in which the LRR exerts its negative regulatory role by stabilizing the ADP-bound state. able without significant loss of virulence func. one of two classes: those that evolve more One of the defining domains of these proteins rapidly and directly bind pathogen Avr is the nucleotide binding site. allowing exchange of ADP for ATP. We have only partial knowl. Dodds and teins. is a general mechanism for NB-LRR pro- (145)]. if that the ATP. Downloaded from arjournals. along with hydrolysis of ATP (4). but sig- stereotype plant R genes as falling into nificant insights have recently been achieved. Binding of ATP to the NBS domain (2) results in activation of signal transduction through the creation of binding sites for downstream signaling molecules and/or the formation of NBS-LRR protein multimers. Note that the eliciting protein may initially interact both with the N-terminal domain and the LRR. The similar findings tion). The ATPase activity of the protein attenuates the signaling response and returns the protein to its resting state. which induces a conformational change in the NB-ARC domain that allows the release of ADP.annualreviews. sugges- against biotrophic pathogens may have a tive of a change of conformation. releasing its signaling potential. Rev. Parts of this model are shown in NB-LRR proteins are the most common type Figure 3. NB-ARC domain (165).

These sites portant for plant immunologists to monitor share homology and likely share mecha. Effectors. rive from an extremely influential paper in a OFF-state LRR Elicitor ARC1 ARC2 ADP Annu.45:399-436. Phytopathol. Downloaded from arjournals. ered NOD/NACHT/CATERPILLAR pro- served regions between these motifs that teins that play roles in animal inflammation. ANRV319-PY45-17 ARI 22 June 2007 19:14 site and LRRs. and R Genes 417 . nisms with animal proteins such as Apaf-1 Aspects of the models in Figure 3 de- and CED-4 and the more recently discov.annualreviews. ON-state (oligomer?) TIR/CC LRR LRR ARC1 ARC1 ARC2 ARC2 ATP ADP NB NB TIR/CC TI R/ CC ADP LRR LRR ARC1 ARC1 ARC2 ATP ARC2 NB NB TIR/CC ATP TIR/CC b Direct pathogen detection Indirect pathogen detection T T N-terminal 1 D 1 D domain D D NBS domain LRR 2 domain 4 4 2 Pi Phosphate Pi Pi D ADP T T T T T ATP Pathogen 3 3 effector Effector target Defense response Defense response www. 2007. (together with the NB) have been called cell death. future research on these animal proteins. It will be im- the NB-ARC domain (88.org • Elicitors.annualreviews. 182). but also some small con. Rev.org Pi NB by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. For personal use only. and immunity (176).

duced upon challenge with Xanthomonas ex- ing with Arabidopsis RPS5. NB-LRR proteins. At What Site Do R Proteins formation for defense signaling (Figure 3) Recognize Pathogens? Is It the LRR (3). a type III-secreted effector idence that the LRR-ARC interaction sup. while other saic virus (135). cently shown that R gene specificity toward it was shown that physical disruption of the pathogens can be mediated by differential ex- LRR-ARC interaction is not required for sig. Rev. Mestre domains of the potato CC-NB-LRR protein & Baulcombe have shown that tobacco N (an Rx physically interact. Rairdan & Moffett fur. providing a means of expression of only the resistant allele is in- signal amplification (138). working with flax The above models for NB-LRR protein Annu.. Phytopathol. For personal use only. present additional evidence that the pres. NB) (120). it was re- LRR into a signal initiation event. 2007. and that stimulation NB-LRR protein) oligomerizes upon recog- by the pathogen Avr protein (PVX coat pro. tion and bring physically associated signaling instances of specificity contributions from 418 Bent · Mackey . work. in which pathogen elici.org L6. stimulating ADP re- lease and ATP uptake at the nucleotide bind- ing site that places the protein in an active con. Ade et al. TIR-NB. ANRV319-PY45-17 ARI 22 June 2007 19:14 which Moffett and colleagues showed that proteins into proximity (78. or TIR. have recently competent conformation (48). genes encoding TIR-NB-LRR or CC-NB- ther support this model (138).g. tion requires a functional nucleotide-binding They proposed a model. Resistant and susceptible alleles that this activity can lead to multiple rounds of rice Xa27 encode identical proteins. tein) to confer resistance against Tobacco mo- tional nucleotide-binding site. sometimes called the site (118). Downloaded from arjournals. ence of a bound nucleotide is required for ulation of the defense signaling activity of the NB-LRR protein to adopt a recognition. Arabidopsis genome. NB. The experi. in addition to over 130 mains (Figure 3a). in loss-of-function N proteins that carry mu- tor causes disruption of intramolecular asso. nition of pathogen. The authors propose instead Avr effector.annualreviews. noted that the portions apparently interact with LRR do.45:399-436. also carries over 50 genes also used domain swaps to localize pathogen for apparent “shorter” R-like proteins lack- recognition specificity to the C-terminal half ing an LRR (e. termining pathogen specificity. Dodds and colleagues. freeing the CC. but of elicitor recognition. alters this interaction. As another theme. Both groups LRR proteins. 138). modulates defense signaling is only starting translates elicitor-induced modulations of the to be explored. Oligomerization could still occur “jackknife” model. pression of an R gene in the presence of the nal initiation. for defense signaling. and/or LRR tifs. provide further ev. However. Meyers et al. and that this oligomeriza- tein) disrupts some of these interactions (122). suggesting that oligomerization is an early domains for interaction with other proteins event in the activation of NB-LRR proteins (122). or CC- of the LRR domain (48. tations in the conserved TIR or RNBS-A mo- ciations. pressing AvrXa27. The possibility that interaction ments with potato Rx suggest that the ARC among heterologous NB-LRR-like proteins region. function do not exclude other means for mod- by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. through its interaction with the LRR. Parts of the discovered a CC-NB-LRR protein that func- ARC domain of these proteins likely fold tions together with N (a TIR-NB-LRR pro- together with the P-loop to form a func. Ec- presses R protein activation and that exposure topic expression of Xa27 was shown to induce to the Avr-derived structure (cleaved PBS1) resistance. that localizes to the plant nucleus (65). 165). However. Peart et al. of NB-LRR Proteins that Is Some models from both plant and animal Recognizing Guarded Host Targets? research also suggest that NB-LRR proteins LRR domains have been implicated in de- act as scaffolds that oligomerize upon activa. 83.

annualreviews. which carry chaperone and proteasome functions. For most R proteins this simply is not known. but that initial binding of elic. Note The proteins with which R proteins (or also that the N terminus of RPS5 interacts MAMP receptors) physically interact are log- with the eliciting PBS1 protein.45:399-436.org recognition complex dependent on the pres. or the host that the LRR does play a key role in elicitor targets of pathogen effectors whose alter- recognition. As What Proteins Are Directly for NB-LRR proteins. They The data suggest that the role of Pto is con. ANRV319-PY45-17 ARI 22 June 2007 19:14 N-terminal regions of NB-LRR proteins have (145). and specificity or activates downstream sig- naling. 192). Effectors. How. naling remain to be discovered (141). and the N ical focal points for further research. 123). FLS2 target the tomato protein kinase Pto. coregulatory molecular switch” (123). and Sgt1. and is a puta- Prf is an NB-LRR protein required for tive adaptor protein that may connect Cf-9 resistance against P. However. making these rectly. Phytopathol. both Extracellular LRRs Work? by controlling preactivation levels of R pro- Multiple R genes have been identified that teins and in contributing to defense signaling encode transmembrane receptor-kinase or (76. volved in protein stabilization (192). when Avr2 physically interacts with and processes a logical place to expect mechanis- inhibits the tomato cysteine protease Rcr3 tic linkages with R proteins (131). The paradigm of NB-LRR Proteins as a Causal Step in direct interaction between ligand and LRR is the Activation of Defense Responses? well established for transmembrane LRR re. Tomato short cytoplasmic tail of Cf-9. tomato Cf-2 carries an extracellular LRR that include an oxidative burst. The terminus of tobacco N interacts with the elic. 2007. R proteins rapidly activate defense responses ever. It is proposed act with an NB-LRR protein. associated gene expression. also play significant roles in en- How Do R Proteins with abling the function of NB-LRR proteins. ceptors and is the likely mechanism by which and it is an obvious area for future research. Rev. and R Genes 419 . For personal use only. CITRX thioredoxin interacts with the also been reported (77. 109.annualreviews. two effector proteins that 9/Avr9-induced defense response (127). Downloaded from arjournals. pathogen Avr proteins that directly inter- iting TMV p50 helicase (3. but other coregulatory interaction that requires Pto ki. Rar1.org • Elicitors. suggest that this stabilizes Xa21 against a de- fined to the regulation of Prf and that the velopmentally controlled proteolytic activity bacterial effectors have evolved to target this that affects disease resistance (188. 25). www. LRR (70). In this complex. both Pto and Prf Xa21 that this autophosphorylation is in- contribute to specific recognition of AvrPtoB. Some functional mechanisms of these proteins were discussed earlier in this review while describing MAMP receptors. there is a glaring gap in our receptor-like proteins with an extracellular current knowledge. those mechanisms are “Downstream” of and Acted Upon by only partially understood. ion channel gating. aspects of how FLS2 itself accomplishes lig- nase activity and N-myristoylation for sig. and Song and colleagues have shown for rice by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. comment: “Pto and Prf associate in a exposed to flagellin-like peptides. ence of Prf. Proteins such as Hsp90. are of itor to R protein may often be mediated by course highly relevant NB-LRR-interacting N-terminal domains (Figure 3). Trans- terminal domain outside of the NBARC-LRR membrane receptor kinase proteins often au- domain and resides in a high molecular weight tophosphorylate their homodimer partners. 88). ation is detected by NB-LRR proteins. Annu. protein ki- but has been implicated as recognizing the nase activity. However. Mucyn undergoes ligand-induced endocytosis when et al. Pto interacts with a unique Prf N. syringae that express and the ACIK1 protein kinase during the Cf- AvrPto or AvrPtoB. Arabidopsis FLS2 binds flagellin (30). and defense- corresponding pathogen Avr2 peptide indi. proteins.

a key goal for future research on plant disease vating and repressing roles in the expres. a situation that raises the MAMP-signaling is not always required. 66). For example. If NB-LRR proteins the cytoplasm but also in the nucleus (156). tion of NB-LRR protein complexes. then Avr resistance against the fungal pathogen Magna- detection by MLA10 is thought to remove this porthe grisea. Identification of direct targets of acti- Annu. a mechanistic linkage with R GENE? MAMP-elicited defenses is proposed (156): The structural range of R gene types was ex- Defenses are elicited by pathogen-derived panded in a significant way with the cloning of MAMPS. possibly because of their func- work with barley MLA10. ARE THERE OTHER TYPES OF tors that otherwise repress defense expression R GENES? WHAT DEFINES AN (156).45:399-436. it remains appropriate to call this an R screens have been conducted but these gen.org scription factors. a gene that confers gene-for-gene extent of MAMP-induced defenses. Downloaded from arjournals. above two questions. which has been effective against barley stem tive defense and an HR. followed Well-controlled studies of MLA10. kinases. leading to highly effec. 43. The question imme. ANRV319-PY45-17 ARI 22 June 2007 19:14 direct linkages were absent until very recent stream targets. Isola- AvrA10 . These include the function of a fused morphic plant genes that control gene-for- NB-LRR-WRKY protein. have now ric identification of interacting proteins. Yeast two-hybrid methods have been mildew pathogen Blumeria graminis (formerly in use for many years with some notable suc- Erysiphe graminis) when those strains express cesses but with relatively low efficiency. WRKY proteins have been vated NB-LRR proteins or other R proteins is by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. 2007. known for many years to play both acti. by MALDI-TOF or other mass spectromet- beit with overexpressed MLA10. do not interact tightly or stably with their A yeast two-hybrid screen revealed interac. gene (and it does not justify premature charac- erally have not revealed the immediate down. yet is not an LRR protein (24). downstream targets. For personal use only. if a gene conferring obvious A dozen years after R genes were first iso. Separate studies have also suggested this Since the work of Harold Flor. other approaches may be tion of MLA10 with certain WRKY tran. Numerous forward genetic mutant served.annualreviews. ever. the nuclear pres. terization of the gene as universally effective 420 Bent · Mackey . Many ef. It was observed that recognition of AvrA10 induces MLA10 association with specific WRKY fac. is shown that this protein exists not only in presently being pursued. How- clear activity of AvrBs3-family pathogen ef. These fectors induce an HR when they are inducibly are but two examples of the mechanistic di- expressed inside plant cells without expression vergence that is increasingly being discovered of other MAMPs. but not all races of a pathogen species). which are thereby expressed more domain rather than an LRR (29). Importantly. this definition may not be entirely use- fector proteins (25. needed. resistance. sion of defense-associated genes (180). have been defined in various ways as the poly- teins. gene disease resistance (specificity for some ence of the tobacco N protein. Rev. disease resistance and encoding an NB-LRR lated. R genes theme of nuclear activity of NB-LRR pro. al. indicating that activated among R proteins. certain WRKY proteins limit the rice Pi-d2. ful. or LRR-kinase protein is found for which ately downstream of R proteins are still largely pathogen race-specificity has not yet been ob- unknown. Phytopathol. an NB-LRR R tional redundancy and/or their lethality when gene product that acts against the powdery mutated. strongly and rapidly. Barley Rpg1. the signaling proteins that act immedi. and the nu. encodes a protein ki- diately arises as to how widely this mechanism nase with similarity to transmembrane LRR- applies to other NB-LRR proteins. rust for over 60 years. Pi-d2 encodes a transmembrane WRKY-mediated check on MAMP-induced receptor-kinase with a B-lectin extracellular defenses.

Effectors. Phytopathol. Downloaded from arjournals. speci. Some researchers have not included FLS2 as an R gene because it does Can the Same R Gene Act Against not confer strong resistance or an HR (62). such as Arabidopsis CPR1. of R proteins are by far the most common croorganisms (51. amples to more clearly establish mechanistic The product of Arabidopsis FLS2 is an trends. adapted to infect Arabidopsis (41). Does this make Pto an R gene? disease resistant. The necessary NB-LRR protein for receptors? AvrPto detection. In this case. one virulent bacterial pathogen (198). and to ex- as first demonstrated for the resistance of hibit specificity for the flagella of some but not tomato against P. Instead. The HR is HR-like necrotic responses to the cognate a common aspect of R gene-mediated defense.annualreviews. ficity for microorganisms.annualreviews.2. all strains of a single pathogen species (164). 59). The resistance. 2007. but the di- generally thought to function against a sin. or bar- encodes an NADPH-dependent toxin reduc. cell death in response to infection. both effector proteins www. confer HR development of an HR (18. Thus. which mutation causes plants to be broadly sence of Pto. or LSD1. is now known to reduce infection by at least conferring gene that is polymorphic be. R genes are sometimes thought of as pathogen race-specificity. virulence is dominant in the these also include genes such as Arabidopsis pathogen due to toxin production. and encode some antimicrobial but genes such as tomato Mi-1 type of LRR-containing protein or require an or wheat H6 confer race-specific resistance LRR protein for their function. syringae expressing avrPto. and action against a Additional questions about R genes have single pathogen species are not defining hall. these genes con- fer resistance against virus or bacteria without fer very strong disease resistance. Hm1 of maize determines for which mutation causes resistance against race-specific disease resistance but does not many pathogen species and constitutive ex- do so through “recognition” of a dominant pression of defenses such as PR-1 (70).org • Elicitors. AvrRpm1 and FLS2-induced defense signaling. act at the duction of an HR is not a requirement of an earliest stages of pathogen detection. For personal use only.1. for example. 147). FLS2 also AvrB (31). ANRV319-PY45-17 ARI 22 June 2007 19:14 and non-race specific!). the in. when mutated. but Mi-1 genes function structures and functional mechanisms present against multiple species of root-knot nema. exhibit R gene. These include non-R genes Annu.45:399-436. and R Genes 421 . Yet Avr gene. pathogen (70. versity of other resistance-associated protein gle type of pathogen. DND1. RPW8. Single R genes are and have received the most study. Prf. ture research. which was generated by introgression of the Should FLS2 now be considered an R gene? Pto kinase from a wild Lycopersicon species And what about other R gene-like MAMP (136). a complex (and intriguing) challenge for fu- tode and aphids. It More than One Avr Gene? is now understood that FLS2 fails to induce Arabidopsis RPM1 acts against two sequence- resistance because bacterial effectors suppress unrelated effector proteins. was apparently present Numerous genes have been identified for in tomato but was nonfunctional in the ab. Does this mean Prf is not an R gene? No. and in some cases control the possible definitions of R genes. and Hm1 RPW8. R gene. naturally occurring alleles of productive to insist on a strict definition of potato Rx or Arabidopsis RPS4 or RPS6 con. LRR-kinase like the product of rice Xa21 (a definite R gene). 191). As a third example. specific resistance but not constitutive broad- There are additional examples that stretch spectrum resistance. Rev. Thus causation of HR. by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. cause pathogen- tase that inactivates the pathogen toxin (86). PMR5 or EDR1. These types against nematodes and insects rather than mi. It may be increasingly un- yet. to con- tween plant accessions also may not be the tribute to resistance against a pathogen not LRR-encoding gene in that defense pathway. In most instances. ley MLO that.org Yes. received partial answers but need further ex- marks of R genes.

or the R proteins may be guarding multi. there can be balanc- Yes: Arabidopsis and soybean both recognize ing selection for both the presence and ab- P. 2007. Phytopathol..g.annualreviews. AvrB. it will in turn reduce positive selection for pres- would not be surprising if the E3 ligase activ. 113. oomycetes and How Fully Conserved Are the viruses in the other (35. Rev. plants may use different R alleles in the host population. tion only in certain Arabidopsis genetic back- Rpt2) target RIN4. The concept of LRR protein to recognize distinct targets of a frequency-dependent selection suggests that single effector. ence of that R allele—resulting in some degree ity of AvrPtoB caused ubiquitylation of multi. 161). 171) suggests that in wild plant Recognized by More than One populations that have not undergone deliber- Mechanism? ate breeding by humans. In another example. RPM1 (114. which teins in addition to RIN4 (32). What might the function of evolved multiple R proteins (RPM1 and RPS2 be in backgrounds in which it does not RPS2) that recognize these distinct modifi. Across Hundreds of Generations and The first example demonstrates convergent Diverse Environments? evolution of two independently derived NB. recognize AvrRpt2? For both RPM1 and RPS2 cations of RIN4 (31). This and other ev- Is the Same Avr Gene Product Ever idence (e. both RPS2 and RPM1 show substantial con- ple targets. AvrRpt2 cleaves multiple Arabidopsis pro. 193)]. For personal use only. and Avr. to shed the corresponding Avr gene. the P. These disparate “Conserved” Types of R Proteins? pathogens may be attacking the same host tar. sence of “conserved” R genes. lection pressure on the pathogen population ple. Shaped at the Population and Species nized by Rsb/Prf (2). The 422 Bent · Mackey . The second exam. now predicted when an R gene product is derived ligands. Arabidopsis HRT/RPP8 family can act against entirely distinct pathogen taxa—nematodes and insects in the one case. there is evidence that the genes cause a fitness penalty to the host in the absence of the cog- nate pathogen (97. 147). but slight vari- Different Pathogen Effector? ations in the LRR permit one allele to func- Multiple effectors (AvrRpm1. 155.org and some Arabidopsis accessions entirely lack Can the Same Host Target Come by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. Citing only two of the available examples. or different alleles of these R genes servation across Arabidopsis accessions. get. Immune System Function Been and a mutant form of AvrPtoB can be recog. 26. syringae that express avrB. Two con- ple demonstrates evolution of a single NB. guarding a conserved host protein. Some pathogen effectors have more common R alleles present stronger se- more than one target in the host. [see e. 155.. showed that the soybean R gene is not an or- tholog of Arabidopsis RPM1 (11).g. a variety of strategies to recognize individual Tomato Mi1 genes and members of the effectors. In turn. Hence. Annu. But Ara- bidopsis carries two allele classes of RPS2. Similarly. of balance (or oscillation) of the frequency of ple plant proteins (82). ANRV319-PY45-17 ARI 22 June 2007 19:14 affect the RIN4 protein “guarded” by RPM1. syringae effector AvrPtoB can How Has R Gene Diversity and be recognized by tomato expressing Pto/Prf. Downloaded from arjournals. as is may encode receptors for distinct pathogen. For exam. 170). Both alleles of RPS2 Under Attack by More than One confer recognition of AvrRpt2. cepts deserve brief mention.45:399-436. Arabidopsis has grounds (15). Ashfield et al. Population-level considerations are a fasci- LRR genes toward recognition of the same nating area for disease resistance research pathogen effector protein. (20. Thus. it appears that Prf Level for Optimized Species Fitness may “guard” two different targets of AvrPtoB.

pecially in non-virus pathogens. but Whereas Others Are Not? their widespread presence on nonthreaten- The above sections have already touched ing microorganisms.annualreviews. and one that merits gets for durable resistance. Rev. in- R genes have remained functionally effective directly recognized effectors that make a ma- despite decades of intensive use (93. and the extent to which a engineering of MAMP recognition may be an directly recognized effector can undergo sub. The rust fungi. 89). suggests that the recognition capacity of in advance by assessing the relative fitness an individual plant’s immune system can be contributions of the corresponding pathogen enhanced by heterozygosity at R gene loci. defenses. important area for future creativity in molec- tle structural changes and retain function. Thus. Es. seem ide- portant idea emerges: the relative durability of ally adapted to evolve resistance-breaking www. Bacteria and and/or long-distance dispersal via wind cur- oomycete pathogens are now known to have rents. 2007. that of heterozygote advan. This might to mutate to prevent activation of resistance by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. other species exhibit sexual reproduction (in- lence or in overall pathogen fitness. widely conserved and essential might seem to be more ideal targets for recognition than dispensable effectors. but many while still contributing to virulence. fector that is recognized directly may be able Annu. Every proteins. jor contribution to pathogen fitness would Nevertheless. re- pathogen fitness. has tempered their value as elici- ognized pathogen effector protein to overall tors of strong defense responses. come available to identify and assess the rele- vant pathogen effectors. The fitness penalty that this loss of tions of some pathogens evolve slowly while a MAMP or effector causes. This may become a very use- also that host populations will benefit from R ful tool if sufficiently inexpensive means be- gene diversity. A second factor will influence the durabil- RESISTANCE DURABILITY AND ity of resistance: the ability of the effector to BREAKDOWN avoid recognition while maintaining its viru- The fourth part of the model from Figure 1 lence activity.annualreviews. The ac. Popula- genome. ular plant breeding. many of which can be sacrificed with pathogen species is different. have limited genome complexity but never- tivity of the effector may be dispensable (at theless have tremendous evolutionary capac- least on that particular host). Downloaded from arjournals.org • Elicitors.45:399-436. ANRV319-PY45-17 ARI 22 June 2007 19:14 second concept. an ef- shows the R gene failing as pathogen popula. seem to be an inevitable event. resistance among R genes might be predicted tage. seemingly provide the best recognition tar- nificant practical issue. The broader evolutionary capacity of the breaking pathogen isolates often entirely pathogen is another trait that strongly in- lose the relevant avirulence gene from their fluences resistance durability (115).org tions evolve to escape detection. and effectors (186). an enduring plague of humankind. should be creasing genetic variation among progeny). Viruses often only minor losses of virulence (6. a strong factor in determining the durability of many generations per season (allowing greater resistance that functions through recognition selection on the relevant host genotypes). MAMPs that are substantial attention in future research. of that MAMP or effector (92). either in viru. For personal use only. or the pathogen ity due to their very large population sizes may have another effector that provides a re. R gene durability remains a sig. 115). However. and short generation times. As was discussed above. resistance. From this an im. animals or mechanical transport (speed- evolved large suites of virulence-enhancing ing genotype spread across large areas). and R Genes 423 . together with the abil- upon two key areas that influence R gene ity of pathogens to suppress MAMP-elicited durability: the relative importance of the rec. Effectors. Phytopathol. MAMPs are indeed a Why Are Some R Genes Durable primary target of plant immune systems. dundant virulence activity.

monitoring of the current races of pathogen in a region to allow pre-emptive breeding and release of varieties with appropriate R Will Molecular Knowledge of genes. suggests that in at least some systems. many possible avenues. plant breeders. For personal use only. Additional approaches exist to enhance the Mixed host approaches. Rev.g. adapted genotypes. Effectors. crops (70). possibly because ary potential can help predict the likely dura. been explored to increase the durability of dis- fective when they are used in rotation. and by the oppo- in Ways that Confer Durable Annu. and growers is needed use molecular markers for R gene alleles to to fully exploit such a system. erly in heterologous systems. MAMP perception can activate very strong ple R genes from wild germplasm and sexually plant defenses that are held in check un- incompatible relatives. The answer is already “yes. in single field. generating previously til activated R proteins remove that negative 424 Bent · Mackey . with ease control (e. have also been shown to pro- ognized effector. 2007. prove plant disease resistance.” Numerous com- effective. and they spread adapted Pursuit of this approach is constrained by the genotypes widely via windborne urediospores. both of which can se- wheat and lettuce (36. tion in the heterologous system. in which lines with durability of genetic resistance. Two practical case studies from pesticides and R genes. For a given pathogen. guide progeny selection while reducing the stances this cooperation has been legally need for more expensive disease tests. in some in. pathogen avirulence for one of the R genes. while avoiding introduction of undesirable al- ple asexual generations that select and amplify leles at other loci of an elite genotype (143). The work of Shen mation. R genes from heterologous species and the A related and very important concept is stacking of multiple R genes that act against that of stacking R genes. beyond as. Combining (or alternating) use of pathogen. or because bility of R gene-based disease control methods of pathogen-independent R protein activa- (115). and R Proteins ing R genes only as needed. Phytopathol. 116) provide excellent lect for insensitive pathogen strains. Downloaded from arjournals. has also examples of how R genes can be more ef. Elicitors.org sition in some quarters against any transgenic Resistance? by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. This is a com- variation within directly recognized effectors. plex undertaking that defies oversimplifica- or the overall evolutionary potential of the tion (124). Equally important is the idea of us. fact that some R genes do not function prop- Assessment of a pathogen’s broader evolution. 14. a single pathogen species are often suggested.. and R protein mechanisms to im- has been achieved through traditional breed. the capacity for structural vide benefits in some settings. the guarded host protein is absent. Careful coordination among pathol. 36).g. the goal is to keep more than one effective and the molecular tools for this type of ef- R gene present in every individual plant so fort are in increasingly common use (e.45:399-436. different resistance genotypes are cultivated sessing the fitness contribution of the rec.. Stacking effectors.annualreviews. Transformation technologies should et al. and removing R Ever Be Useful? genes from use before they become widely in. A larger challenge will be to use our even if individuals are present that have lost growing understanding of MAMPs. Use of mandated. Investment in transgenic stacking of R genes also has been limited by fear that sufficient resistance dura- How Can We Make or Use R Genes bility will not be achieved. that pathogen reproduction will be restricted 102). There are ing and now is possible by plant transfor. ANRV319-PY45-17 ARI 22 June 2007 19:14 isolates because they couple complex genomes unattainable combinations of stacked R genes and annual sexual reproduction with multi. mercial and public plant breeding programs ogists. allow identification and deployment of multi.

45:399-436. Some NB-LRR proteins are present in both the cytoplasm and the nucleus. Effectors. but other proteins types can also be classified as R proteins. adapted pathogens into “nonhost” pathogens. 5. Because pathogen effector proteins often contribute to virulence by suppressing or dis- rupting host defense responses. The receptors for these MAMPs have so far tended to be transmembrane proteins that have an extracellular leucine-rich repeat (LRR) domain. 2. Many NB-LRR R proteins are apparently maintained in an ADP-bound “off ” state by interactions of LRR and NB-ARC domains. and R Genes 425 .org erologous plant species. This delicately balanced sys.annualreviews. Elicitation disrupts these interactions and allows ADP release/ATP binding. Phytopathol. R proteins are most commonly intracellular NB-LRR proteins or extracellular LRR- carrying receptors. Downloaded from arjournals. some plants express R pro- teins that directly or indirectly recognize effectors and activate strong defenses. R proteins may recognize pathogen effectors by direct physical interaction. possibly tion of effectors that make a major virulence allowing modification of those targets toward contribution may allow identification of the insensitivity. As a separate approach. but apparently are then detected by the LRR do- main. but indirectly recognized effectors in many cases can escape detection only by ceasing virulence activity. thereby converting goals.annualreviews. pathogens express effectors that suppress basal defenses. identifica. it will remain important that host targets may allow placement of those host the brightest minds and ample funding be targets and their guardian R proteins into het. As our un- improved R genes that recognize effector do. or they may recognize them indirectly by sensing the host proteins upon which effectors have acted. 7. the study of effectors is revealing fascinating pathogen adaptation to host biology and identifying specific plant processes that contribute to disease resistance. Directly recognized targets as QTL markers for plant breeding. and some pathogens modify or eliminate the effectors that the host can recognize so that the pathogen regains at least some virulence on hosts that express these R proteins. by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. pathogen virulence and plant immunity con- The understanding that effectors often attack tinues to grow. tem presents many opportunities for engi. or use of the genes for those host best R genes to utilize. effector proteins might be used to screen for These are just a few possible ideas. 4. SUMMARY POINTS 1. Effectors can allow identification of host pro- neering.org • Elicitors. Directly recognized effectors may escape detection by altering their shape while re- taining virulence function. derstanding of the molecular mechanisms of mains that can tolerate little or no change. A new paradigm for defense activation has emerged in which plants recognize microbe-associated molecular patterns (MAMPs) and thereby activate basal defenses. cesses perturbed to promote disease. For personal use only. 2007. opening the protein for defense-signaling protein- protein interactions. Rev. A limited number of MAMPs have been defined. attracted both to basic and applied research Annu. 3. Some effectors or effector products bind initially to N-terminal domains of the NB-LRR protein. ANRV319-PY45-17 ARI 22 June 2007 19:14 regulation (156). 6. www.

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Dolja p p p p p p 73 Cell Wall-Associated Mechanisms of Disease Resistance and Susceptibility Ralph Hückelhoven p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p101 Genomic Insights into the Contribution of Phytopathogenic Bacterial Plasmids to the Evolutionary History of Their Hosts George W. AR319-FM ARI 13 July 2007 17:17 Annual Review of Phytopathology Contents Volume 45. F. B. Ben J. 2007. van den Burg. Obradovic. De Wolf and Scott A. Rev. Culver and Meenu S. Martelli. Jan F. James Cook p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Noel T. 2007 Annu. Adams. Momol p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p245 v . R. L E.45:399-436. Ole Becker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p153 Safety of Virus-Resistant Transgenic Plants Two Decades After Their Introduction: Lessons from Realistic Field Risk Assessment Studies Marc Fuchs and Dennis Gonsalves p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p173 Disease Cycle Approach to Plant Disease Prediction Erick D. T. Phytopathol. and M.B. Balogh.annualreviews. Sundin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p129 Identifying Microorganisms Involved in Specific Pathogen Suppression in Soil James Borneman and J. Keen—Pioneer Leader in Molecular Plant Pathology Alan Collmer and Scott Gold p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 25 Structure and Function of Resistance Proteins in Solanaceous Plants Gerben van Ooijen. Harrold A. Padmanabhan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p221 Bacteriophages for Plant Disease Control J. Jackson. Jones. For personal use only. and Frank L. Takken p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 43 Family Flexiviridae: A Case Study in Virion and Genome Plasticity Giovanni P. Cornelissen. Downloaded from arjournals. Isard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p203 Virus-Induced Disease: Altering Host Physiology One Interaction at a Time James N. Michael J.C. A. Iriate. B. W.org Tell Me Again What It Is That You Do by NORTH CAROLINA STATE UNIVERSITY on 03/12/08. Kreuze. and Valerian V.

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