APRIL

Jurg Tschopp*
Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, Epalinges, CH-1066,
Switzerland
* corresponding author tel: ‡41 21 692 5738, fax: ‡41 21 692 5705, e-mail: jurg.tschopp@ib.unil.ch.
DOI: 10.1006/rcwy.2000.05011.

SUMMARY eight  strands in its extracellular domain, which are

APRIL is a member of the TNF family. While
transcripts of APRIL are of low abundance in normal
tissues, high levels of mRNA are detected in trans-
formed cell lines, and in human cancers of the colon,
thyroid, and lymphoid tissues in vivo. The addition of
recombinant APRIL to various tumor cells stimulates
their proliferation. Moreover, APRIL-transfected
NIH 3T3 cells show an increased rate of tumor
growth in nude mice when compared with the paren-
tal cell line. The receptor of APRIL is currently
unknown. APRIL may be implicated in the regula-
tion of tumor cell growth.
BACKGROUND
Discovery
The discovery of APRIL arose from studies aimed at
identifying novel members of the TNF ligand by
screening public databases using a profile search
(Bucher et al., 1996). Several cDNA clones were
identified encoding a novel protein of 250 amino acids
with significant sequence homology to known mem-
bers of this family (Hahne et al., 1998).
Structure
The absence of a signal peptide suggests that APRIL
is a type II membrane protein that is typical of the
members of the TNF ligand family. Based on the
known structure of the homologous lymphotoxin  The APRIL gene is found adjacent to that for
(Banner et al., 1993), APRIL is predicted to contain
folded into an antiparallel  sandwich structure.
Main activities and
pathophysiological roles
Recombinant soluble APRIL leads to an increased
proliferation of various tumor cell lines, including
Raji B cells, Jurkat T cells, and MCF-7 carcinoma
cells. NIH 3T3 cells overexpressing full-length APRIL
proliferate faster. When injected into nude mice,
APRIL-expressing NIH 3T3 cells form tumors
significantly faster than do parental NIH 3T3 cells
(Hahne et al., 1998). Together with the observation
that APRIL mRNA is increased in tumor cell lines
and in metastatic tumors, this suggests that increased
APRIL expression may be involved in tumorigenesis.
GENE AND GENE REGULATION
Accession numbers
GenBank:
Human gene: AF046888
Chromosome location
The gene has been localized to chromosome 17p13.
Relevant linkages
TWEAK.
500 Jurg Tschopp

Cells and tissues that express Discussion of crystal structure

the gene No crystal structure is available. However, the crystal
Human APRIL mRNA is found in peripheral blood structure of APRIL is expected to be homologous to
lymphocytes (PBLs) and prostate gland. Expression is that of lymphotoxin , CD40L, and TNF, for which
particularly high in tumor tissues (thyroid and colon structural information is available (being an elon-
carcinoma, and lymphoma), and in cell lines (promye-
locytic leukemia, HL-60; HeLa cell S3; chronic
myelogenous leukemia, K562; lymphoblastic leuke-
mia, MOLT-4; Burkitt's lymphoma, Raji; colorectal
adenocarcinoma, SW480; lung carcinoma, A459;
melanoma, G361).
PROTEIN
Sequence
The protein sequence of APRIL is shown in Figure 1.
Description of protein
APRIL is a type II membrane protein lacking a signal
peptide.
gated, antiparallel  pleated sheet sandwich with a
`jelly-roll' topology, three monomers associating inti-
mately about a 3-fold axis of symmetry to form a
compact, bell-shaped trimer) (Eck and Sprang, 1989;
Banner et al., 1993; Karpusas et al., 1995).
Important homologies
APRIL is a member of the TNF ligand family
(Figure 2).
Posttranslational modifications
There is a putative glycosylation site at asparagine 124.
The extracellular region is processed by an
unknown protease (possibly furin), which cleaves
in a highly basic region of the stalk region
(RKRRAVLTQKQKK). The receptor-binding
domain of APRIL is thereby released.

Figure 1 Protein sequence of APRIL. The transmembrane domain is underlined.

Sequence
Transmembrane domain underlined.
1 MPASSPFLLA PKGPPGNMGG PVREPALSVA LWLSWGAALG AVACAMALLT QQTELQSLRR
61 EVSRLQGTGG PSQNGEGYPW QSLPEQSSDA LEAWENGERS RKRRAVLTQK QKKQHSVLHL
121 VPINATSKDD SDVTEVMWQP ALRRGRGLQA QGYGVRIQDA GVYLLYSQVL FQDVTFTMGQ
181 VVSREGQGRQ ETLFRCIRSM PSHPDRAYNS CYSAGVFHLH QGDILSVIIP RARAKLNLSP
241 HGTFLGFVKL

Figure 2 Alignment comparing seven members of the TNF ligand family.

APRIL 117 VLHLVPINATSKDDS..........DVTE

VMWQPA.LRRGRGLQA....QGYGVRIQDAGVYLLYSQVLFQDVT..........FTMGQV
TNFa 89 VAHVVANPQAEGQ................LQWLNR..RANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPS....THVLLTHTI
TXa 64 AAHLIGDPSKQNS................LLWRAN..TDRAFLQDGFSLSNNSLLVPTSGIYFVYSQVVFSGKAYSPKATSSPLYLAHEV
FASL 146 VAHLTGKSNSRSMP...............LEWEDT..YGIVLLSGVKY.KKGGLVINETGLYFVYSKVYFRGQSCN......NLPLSHKV
TRAIL 123 AAHITGTRGRSNTLSSPNSKNEKALGRKINSWESSR.SGHSFLSNLHL.RNGELVIHEKGFYYIYSQTYFRFQEEIK....ENTKNDKQM
TWEAK 143 AAHYEVHPRPGQDGAQAGV......DGTVSGWEKARINSSSPLRYNR..QIGEFIVTRAGLYYLYCQVHFDEGKAVY..LKLDLLVDGVL
TRANCE 164 FAHLTINATDIPSGSH.........KVSLSSWYHD..RGWGKISNMTF.SNGKLIVNQDGFYYLYANICFRHHETSGDLATEYLQLMVYV

PRIL 182 VSREGQG...RQETLFRCIRSMP........SHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKL

TNFa 157 SRIAVSY...QTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL
TXa 136 QLFSSQY...PFHVPLLSSQKMV......YPGLQEPWLHSMYHGAAFQLTQGDQLSTHTDGIPHLVLSP.STVFFGAFAL
FASL 212 YMRNSKY...PQDLVMMEGKMMS......YCTTGQMWARSSYLGAVFNLTSADHLYVNVSELSLVNFEE.SQTFFGLYKL
TRAIL 189 VQYIYKYTSYPDPILLMKSARNS.....CWSKDAEYGLYSIYQGGIFELKENDRIFVSVTNEHLIDMDH.EASFFGAFLV
TWEAK 223 ALRCLEE...FSATAASSLGP...............QLRLCQVSGLLALRPGSSLRIRTLPWAHLKAAP.FLTYFGLFQV
TRANCE 242 TKTSIKI...PSSHTLMKGGSTK.....YWSGNSEFHFYSINVGGFFKLRSGEEISIEVSNPSLLDPDQ.DATYFGAFKV

CELLULAR SOURCES AND
TISSUE EXPRESSION
Cellular sources that produce
Many cell lines express APRIL mRNA. There is no
report on protein expression.
IN VITRO ACTIVITIES
In vitro findings
APRIL accelerates the growth of many cell lines.
Bioassays used
The bioassay used is an increased proliferation rate of
Jurkat cells (Hahne et al., 1998).
APRIL 501
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