Professional Documents
Culture Documents
The proteostasis network (PN) regulates protein synthesis, The cellular proteostasis network
folding, transport, and degradation to maintain proteome At the single-cell level, the PN comprises the molecular machin-
eries and systems that are essential for all stages of protein bio-
integrity and limit the accumulation of protein aggregates,
genesis and breakdown (Balch et al., 2008). The generic view of
a hallmark of aging and degenerative diseases. In multi- the eukaryotic PN (Fig. 1) encompasses the following processes
cellular organisms, the PN is regulated at the cellular, tis- (Labbadia and Morimoto, 2015a): (a) translation, controlled by
sue, and systemic level to ensure organismal health and the ribosome and associated factors that regulate the synthesis
of the nascent polypeptide chain; (b) protein folding, assisted
THE JOURNAL OF CELL BIOLOGY
longevity. Here we review these three layers of PN regula- cotranslationally and posttranslationally by molecular chaper-
tion and examine how they collectively maintain cellular ones and cochaperones through cycles of substrate binding and
homeostasis, achieve cell type-specific proteomes, and release; (c) protein trafficking in the cytosol, across biological
membranes, and within subcellular compartments; and (d) pro-
coordinate proteostasis across tissues. A precise under-
tein degradation by the ubiquitin-proteasome system (UPS),
standing of these layers of control has important implica- the autophagy/lysosomal pathways, and cellular proteases. The
tions for organismal health and could offer new therapeutic PN extends to all subcellular compartments, such as the ER,
approaches for neurodegenerative diseases and other mitochondria, and nucleus, which possess generic as well as
dedicated machineries that are specific to the respective micro-
chronic disorders related to PN dysfunction.
environment (Kaushik and Cuervo, 2015). These subcellular
networks are highly interconnected and communicate with each
Introduction other to promote proteostasis across the cell (Wolff et al., 2014).
Causes of protein misfolding.As illustrated in
Proteome integrity is maintained by the proteostasis network Fig. 1, imbalance in the overall flux of proteostasis, however
(PN), which consists of interconnected systems that regulate transient, promotes off-pathway events that lead to the forma-
protein synthesis, folding, transport, and degradation in every tion of damaged, misfolded, or aggregated protein species,
cell. The functionality of this network declines during aging, which can be toxic to the cell (Balchin et al., 2016). Protein
thus compounding the risk for diseases related to proteostasis misfolding occurs continuously because of the inherently er-
dysfunction, such as neurodegenerative diseases, cardiomy- ror-prone nature of biological systems. For example, errors in
opathies, and metabolic disorders (Balch et al., 2008). Studies transcription, splicing, and translation can result in unstable or
in yeast and tissue culture have provided fundamental insights aberrant protein variants. The highly crowded cellular environ-
into the molecular mechanisms of PN function and regulation ment favors nonnative interactions during protein synthesis, re-
within single cells (Balchin et al., 2016). Multicellular organ- folding, and conformational changes (Ellis and Minton, 2006).
isms, however, consist of different cell types that are struc- The presence of intrinsically disordered regions within native
turally and functionally diverse, reflecting distinct proteomes proteins, as well as conformational changes associated with
(Uhlén et al., 2015). Thus, the composition and functionality protein function or posttranslational modifications, and the for-
of the PN must be tailored to meet the specific needs of each mation of multimeric complexes, also put proteins at risk for
cell and tissue type throughout development and adulthood. adopting alternate nonnative structures (Uversky et al., 2008;
Differentiation, specialization, and spatial organization of cells Prabakaran et al., 2012). In addition to intracellular causes, pro-
in complex organisms also influence the ability of individual teotoxic stress induced by environmental fluctuations and phys-
cells to sense and respond to stressful stimuli. Therefore, trans- iological stimuli can rapidly affect the composition or integrity
cellular mechanisms are in place to orchestrate PN functionality of the proteome. Off-pathway events are counteracted by chap-
across organs and tissues (van Oosten-Hawle and Morimoto, erone machineries, which refold nonnative species and resolve
2014). Here, we review the differential scales of proteostasis protein aggregates, and degradation pathways, which destroy
regulation from the cellular to the organismal level and discuss misfolded and aggregated proteins (Balchin et al., 2016).
implications for human health.
Correspondence to Richard I. Morimoto: r-morimoto@northwestern.edu
© 2017 Sala et al. This article is distributed under the terms of an Attribution–Noncommercial–
Abbreviations used: ALS, amyotrophic lateral sclerosis; HSR, heat shock re- Share Alike–No Mirror Sites license for the first six months after the publication date (see
sponse; OxR, oxidative stress response; PN, proteostasis network; sHSP, small http://www.rupress.org/terms/). After six months it is available under a Creative Commons
heat shock protein; TPR, tetratricopeptide repeat; UPR, unfolded protein re- License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at
sponse; UPS, ubiquitin-proteasome system. https://creativecommons.org/licenses/by-nc-sa/4.0/).
Cell-nonautonomous control of the UPR.Evi- in Drosophila muscle influences proteostasis in retina, brain,
dence from multiple organisms indicates that the UPRER and the and adipose tissues (Demontis and Perrimon, 2010).
UPRmt are also under cell-nonautonomous control. Perturbation Organismal health and longevity is also controlled by the
of the mitochondrial electron transfer chain increases lifespan reproductive system in C. elegans (Hsin and Kenyon, 1999).
in both invertebrates and rodents through the activation of the Signaling from the germ stem cells was shown to repress so-
UPRmt (Liu et al., 2005; Copeland et al., 2009; Durieux et al., matic cell stress responses and proteostasis capacity during early
2011). Neuron-targeted disruption of mitochondrial function adulthood, at the onset of reproduction (Shemesh et al., 2013;
can lead to cell-nonautonomous activation of the UPRmt in non- Labbadia and Morimoto, 2015b). Germ stem cell–mediated reg-
neuronal tissues in C. elegans (Durieux et al., 2011). Mild per- ulation of the HSR in somatic tissues is associated with the ac-
turbation of the electron transfer chain in Drosophila muscle cumulation of repressive chromatin marks at heat shock genes,
also leads to a systemic response, which involves repression of which restricts HSF1-mediated induction of stress-responsive
insulin signaling and has beneficial effects on organismal health genes (Labbadia and Morimoto, 2015b). Enhanced proteosta-
and lifespan (Owusu-Ansah et al., 2013). Similarly, the UPRER sis and extended lifespan in animals devoid of a germline rely
is induced in peripheral tissues when active XBP1 is overex- on multiple transcription factors, including DAF16, PHA4, and
pressed in neurons, which likely depends on neuronal activity SKN1, in addition to HSF1 (Lin et al., 2001; Lapierre et al.,
(Taylor and Dillin, 2013). Induction of the UPRER in nonneuro- 2011; Steinbaugh et al., 2015). Removal of the germline also
nal tissues during infection is mediated by sensory neurons in increases lifespan in Drosophila through modulation of insulin
C. elegans, suggesting an organismal stress response to patho- signaling, indicating that regulation of health and longevity by
gens (Sun et al., 2011). Cell-nonautonomous regulation of cel- the reproductive system is conserved (Flatt et al., 2008).
lular stress responses has also been observed in mice, where Most of our understanding of cell-nonautonomous con-
overexpression of active XBP1 in pro-opiomelanocortin neu- trol of proteostasis comes from studies in invertebrate model or-
rons leads to activation of the UPRER in the liver ganisms. However, evidence is starting to emerge that a similar
(Williams et al., 2014). process exists in mammals, where circulating factors have long
Cell-nonautonomous regulation in longevity been known to distantly regulate multiple aspects of physiology
pathways.Several longevity pathways that increase stress re- (Williams et al., 2014). Further investigations are required to
sistance and proteostasis have been shown to be regulated cell identify these factors and the pathways that they regulate, and to
nonautonomously in invertebrates. Dietary restriction increases determine whether they are conserved in humans.
lifespan and proteostasis in C. elegans, Drosophila, and mice
(Mair and Dillin, 2008). The effects of dietary restriction on Implications for neurodegenerative diseases
organismal health and longevity have been linked to an isoform Although the dynamic nature of the PN allows organisms
of the oxidative stress transcription factor SKN1, which is spe- to buffer acute and chronic stresses, proteostasis capacity is
cifically expressed in a subset of sensory neurons in C. elegans limited and declines during aging. Many age-related pathol-
(Bishop and Guarente, 2007). Intestinal expression of DAF16/ ogies, and in particular neurodegenerative diseases such as
FOXO, the effector of the longevity insulin/IGF1 signaling Alzheimer’s disease, Parkinson’s disease, and amyotrophic
pathway, also acts distantly on muscle tissue to enhance proteo- lateral sclerosis (ALS), are characterized by the accumulation
stasis (Zhang et al., 2013). Similarly, overexpression of dFOXO of abnormal proteins, which is associated with proteostasis