fig1

Figure 1. The proteostasis network. The folding of newly synthesized proteins is a complex mechanism that involves multiple steps. ~30% of nascent proteins, named DRiPs, have an inherent inefficiency of protein folding and undergo degradation within minutes from synthesis. Most proteins achieve a functional folded state. However, many are the causes that trigger spontaneous unfolding. These changes in conformation are recognized by the cell’s protein quality control machinery with activation of an unfolded protein response (UPR). The three branches of the UPR (PERK, IRE, ATF6) help restore protein homeostasis partially by increasing the synthesis of chaperone proteins. By association with exposed hydrophobic domains, chaperones like BiP (GRP78), favor refolding. Alternatively, they can facilitate the recognition of abnormal proteins, leading to their ubiquitylation by E3 and their degradation through the proteasome. If the ER stress cannot be mitigated and homeostasis cannot be reestablished, UPR induces cell death.