Figure 1.
Overview of the proteostasis network (PN). The human PN must ensure proteome stability across cellular compartments (not drawn to scale). Molecular chaperones of the HSP70 (blue spheres), HSP40/DNAJ (red spheres), and HSP90 (green spheres) families are found in all major cellular compartments and cooperate with cochaperones (gray spheres) to promote folding of nascent chains, assembly of protein complexes, refolding of misfolded clients (serrated red spheres), or degradation of terminally misfolded substrates by the proteasome. Small heat shock protein (sHSP) homo-oligomers bind misfolded proteins and maintain them in a folding-competent state for the HSP70 machinery. If refolding is unsuccessful, cooperation with the nucleotide exchange factor Bcl2-associated athanogene 1 (BAG1) and the E3 ubiquitin ligase C terminus of HSC70-interacting protein (CHIP) can direct substrates to the proteasome. The HSP60 family of chaperones is crucial for mitochondrial proteostasis (in conjunction with the “lid” cochaperone HSP10) and for folding of cytoskeletal components via the TCP-1 ring complex (TRiC). Certain chaperones and cochaperones perform specialized or compartment-specific functions (orange spheres). For example, in the endoplasmic reticulum (ER), protein disulfide isomerase (PDI) and ER oxidoreductin 1 (ERO1) cooperate to promote disulfide bond formation, while calnexin (CANX) and calreticulin (CALR) perform calcium-dependent folding of substrates. Upon protein misfolding, specific stress response pathways such as the heat shock response (HSR) and unfolded protein responses of the ER (UPRER) and mitochondria (UPRmito) can boost chaperone levels. Occasionally, misfolded proteins can form aggregates that can be deleterious to cells. HSP110 cooperates with HSP70/HSP40 to act as a disaggregase. Alternatively, large aggregates can be degraded by the lysosome through autophagy. A modification of this pathway (mitophagy) can also be used to remove old or damaged mitochondria. Gray arrows indicate pathways that should occur only at low levels in healthy cells. Abbreviations: DUB, deubiquitinating enzyme; ERAD, ER-associated degradation; mRAC, mammalian ribosome-associated complex; NAC, nascent polypeptide chain–associated complex; Ub, ubiquitin.