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Review
. 2020 Aug;215(4):889-901.
doi: 10.1534/genetics.120.301283.

Organismal Protein Homeostasis Mechanisms

Thorsten Hoppe  1   2 , Ehud Cohen  3
Affiliations
Review

Organismal Protein Homeostasis Mechanisms

Thorsten Hoppe et al. Genetics. 2020 Aug.

Abstract

Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a conserved network of quality control pathways that orchestrate the biogenesis of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful proteins by selective degradation. Nevertheless, the proteostasis network has a limited capacity and its collapse deteriorates cellular functionality and organismal viability, causing metabolic, oncological, or neurodegenerative disorders. While cell-autonomous quality control mechanisms have been described intensely, recent work on Caenorhabditis elegans has demonstrated the systemic coordination of proteostasis between distinct tissues of an organism. These findings indicate the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome, opening a new door to define novel therapeutic targets for protein aggregation diseases. Here, we provide an overview of individual protein quality control pathways and the systemic coordination between central proteostatic nodes. We further provide insights into the dynamic regulation of cellular and organismal proteostasis mechanisms that integrate environmental and metabolic changes. The use of C. elegans as a model has pioneered our understanding of conserved quality control mechanisms important to safeguard the organismal proteome in health and disease.

Keywords: C. elegans; WormBook; autophagy; chaperone; intertissue signaling; proteasome; proteostasis; proteotoxicity; stress response; ubiquitin; unfolded protein response.

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Figures

Figure 1
Figure 1
The proteostasis network (PN). The folding of nascent polypeptides is cotranslationally assisted by specialized chaperones such as the nascent polypeptide-associated complex (NAC) (I). Interacting chaperones further assist the folding of the newly synthesized polypeptide (II), and additional components of the PN safeguard the integrity of post-translational modifications (III) and intermolecular interactions (IV). The fully processed protein is shuttled to its target organelle where it executes enzymatic or structural functions (V). When the mature protein is damaged or should be recycled, it undergoes degradation by the ubiquitin (Ub)/proteasome system (UPS) (VI) or autophagy (VII). Even under normal conditions a fraction of the nascent polypeptides fail to fold properly (VIII). These misfolded proteins can be refolded by specialized chaperones to attain their correct spatial structures and become functional. Molecules that fail to fold properly are degraded by the 26S proteasome (IX). Upon accumulation, aggregation-prone, misfolded proteins form toxic oligomers (X) that can be detoxified either by disaggregation (XI) and subsequent UPS-mediated degradation (XII), or by protective hyperaggregation (XIII). Under certain conditions, these aggregates are transported to cellular deposition sites (XIV), to subsequently be degraded by the 26S proteasome (XV) or by autophagy (XVI).
Figure 2
Figure 2
Stress-response mechanisms. The accumulation of protein aggregates in different cellular organelles activates organelle-specific stress-response mechanisms that modulate gene expression to support the restoration of proteostasis. (A) Heat exposure leads to the accumulation of aggregated proteins within the cytosol and to the activation of the heat-shock response (HSR). A cytosolic chaperone, a member of the HSP70 family, recognizes protein aggregates (A-I) and mediates the translocation of the transcription factor HSF-1 into the nucleus (A-II), where it trimerizes and regulates the expression of its target genes (A-III). The resulting transcripts migrate to the cytosol (A-IV) and the translated proteins, mostly chaperones (A-V), support proteostasis maintenance (A-VI). (B) A similar mechanism, known as the mitochondrial unfolded protein response (UPRmt), is caused by metabolic impairment such as oxidative stress or malfunction of the electron transport chain in mitochondria. Increased levels of protein aggregates are detected by the HSP70 chaperone, HSP-6 (B-I), which induces the migration of the transcription factor ATFS-1 into the nucleus (B-II). In the nucleus, ATFS-1 teams up with UBL-5 and the chromatin modulator DVE-1 to change the expression levels of its target genes (B-III). The resulting messenger RNA transcripts are exported into the cytosol (B-IV) where they are translated (B-V) and transported into mitochondria to restore proteostasis. (C) The ER has three canonical unfolded protein response mechanisms (UPRER) that are activated upon accumulation of aggregated proteins within the ER lumen. Similarly to the HSR and the UPRmt, a member of the HSP70 family named BiP identifies misfolded proteins and activates IRE-1 (C-I), which initiates a process of splicing and translation of the transcription factor XBP-1 (C-II). XBP-1 migrates to the nucleus (C-III) where it activates the expression of genes that encode for ER chaperones and components of the ER-associated protein degradation (ERAD) pathway. The protein aggregation-mediated ER stress further activates the kinase PERK, which has two key functions (C-V): it promotes the migration of ATF-4 into the nucleus (C-VI) where it regulates its target gene networks and phosphorylates eIF2α. The phosphorylation of eIF2α inhibits the translation of proteins that require the assistance of chaperones to fold properly, thereby easing the workload of the ER-resident proteostasis network. The third UPRER mechanism that is activated upon ER stress involves ER membrane-bound ATF-6 (C-VII), which is shuttled to the Golgi apparatus, where it is proteolytically cleaved (C-VIII) enabling shuttling into the nucleus (C-IX). In the nucleus, it enhances the expression of xbp-1 and additional target genes encoding ERAD components. The transcripts that are formed as a result of the activities of XBP-1, ATF-4, and ATF-6(N) are exported to the cytosol (C-X) and translated by the ribosome. The resulting ER-resident chaperones as well as ERAD components are transported into the ER to maintain proteostasis, either by refolding of aggregated proteins (C-XI) or proteasomal degradation of terminally misfolded proteins (C-XII).
Figure 3
Figure 3
Organismal coordination of proteostasis networks. Schematic illustration of the organismal cross talk between cellular stress-response pathways in C. elegans. Perturbation of proteostasis in distinct cellular compartments results in cell-autonomous transcriptional responses termed the heat-shock response (HSR), the ER unfolded protein response (UPR), and the mitochondrial UPR, which mediate adaptive regulation of chaperones and proteolytic degradation pathways. Induction of these inducible gene expression programs is defined by the transcription factors HSF-1, XBP-1, and ATFS-1, which bind to specific regulatory elements on the DNA. Importantly, cellular responses can also be communicated to distal tissues by endocrine signaling, which integrates sensory perception of environmental insults, governed by serotonergic (blue), thermosensory (yellow), chemosensory (green), and additional neurons (gray). The Glial cells (light blue) are also involved in the orchestration of proteostasis. Muscle and intestinal cells also communicate by transcellular chaperone signaling (TCS), which coordinates chaperone activity across tissues. Finally, germ cells signal to other tissues to promote stress resistance and proteostasis. Thus, distal tissues are prepared to mitigate proteotoxic conditions that challenge the entire organism. Dashed gray lines indicate putative cross-communication between muscle (red), intestine (ocher), and the germ line (violet).
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