Shaping proteostasis at the cellular, tissue, and organismal level

Abstract

The proteostasis network (PN) regulates protein synthesis, folding, transport, and degradation to maintain proteome integrity and limit the accumulation of protein aggregates, a hallmark of aging and degenerative diseases. In multicellular organisms, the PN is regulated at the cellular, tissue, and systemic level to ensure organismal health and longevity. Here we review these three layers of PN regulation and examine how they collectively maintain cellular homeostasis, achieve cell type-specific proteomes, and coordinate proteostasis across tissues. A precise understanding of these layers of control has important implications for organismal health and could offer new therapeutic approaches for neurodegenerative diseases and other chronic disorders related to PN dysfunction.

Figure 1.

Overview of cellular proteostasis. Proteostasis encompasses the cellular processes that guide the synthesis, folding, transport, and degradation of all proteins. It is regulated by the PN, which consists of the translation machinery, molecular chaperones, UPS, and autophagy to maintain the overall flux of proteostasis (black arrows). Nonnative conformations produced by off-pathway events (red arrows) are recognized by quality control mechanisms to prevent the accumulation of abnormal proteins in the cell. Misfolded and aggregated proteins are either redirected to the folding pathway through disaggregation and refolding (blue arrows) or targeted to degradation systems (gray arrows).

Figure 2.

Tissue expression profile of the human proteome and chaperome genes. Analysis of mRNA expression data from the Human Protein Atlas (Uhlén et al., 2015). (A) Combined expression data of 20,358 human protein-coding genes in 32 tissues are represented as the fraction of total transcripts encoding soluble, membrane-associated, secreted, mitochondrial-encoded and genes with isoforms belonging to more than one category. For each category, the number of genes included in the analysis is indicated in brackets. (B) Combined expression data of genes corresponding to molecular chaperones and cochaperones of the human chaperome (Brehme et al., 2014) in 32 tissues. The chaperome consists of the following groups of chaperones and cochaperones found in all compartments: HSP40, HSP70, HSP90, HSP60, prefoldin (PFD), sHSPs, and TPR domain-containing proteins, as well as organelle-specific chaperones of the ER (ER-specific) and mitochondria (MITO-specific, all nuclear encoded). It should be noted that the groups defined as HSP70 and HSP90 include both HSP chaperones and associated factors. Of the 332 chaperome genes defined by Brehme et al. (2014), 324 were present in the Human Protein Atlas dataset. (C) Tissue-specific expression of the proteome and the chaperome in selected tissues corresponding to bone marrow, liver, pancreas, skin, brain, small intestine, skeletal muscle, heart muscle, and adipose tissue. Expression data for the proteome and chaperome are represented as in A and B, respectively.

Figure 3.

Differential scales of proteostasis regulation in multicellular organisms. The PN is regulated at multiple scales from the cellular to the organismal level, which is illustrated here for the human chaperome (refer to Fig. 2 for details). At the cellular level, the PN consists of the molecular machineries required in all compartments to maintain proteostasis (top). Tissue-specific regulation of PN components tailors PN activity to tissue-specific functions (middle). Recent discoveries in invertebrate and vertebrate models suggest that the PN is also controlled across tissues and organs by neuronal activity and intertissue communication to regulate proteostasis at the organismal level (bottom).