1. Figure 1 ER stress and associated lines of defence
Figure 1 | ER stress and associated lines of defence. Under endoplasmic reticulum (ER) stress, the cell activates several well-orchestrated processes to restore ER homeostasis. The first line of defence against the accumulation of misfolded proteins in the ER lumen is ER-associated degradation (ERAD), a mechanism by which misfolded proteins are retrotranslocated to the cytosol, ubiquitylated and degraded by the proteasome. When the misfolded protein load is too high, the unfolded protein response (UPR) starts with the activation of three transmembrane effectors: eukaryotic translation initiation factor 2α kinase 3 (PKR-like ER kinase; PERK), serine/threonine-protein kinase/endoribonuclease IRE1 (IRE1) and cyclic AMP-dependent transcription factor ATF-6α (ATF6). The activation of these three effectors is initiated by the relocation of the chaperone binding immunoglobulin protein (BiP) from the ER membrane to the ER lumen where it associates with unfolded proteins. The role of the UPR is to re-establish ER homeostasis by reducing de novo protein synthesis and improving the folding and clearance capacity of the ER. PERK-mediated eukaryotic translation initiation factor 2α (eIF2α) phosphorylation inhibits translation except for cyclic AMP-dependent transcription factor ATF-4 (ATF4). IRE1-mediated activation of X-box-binding protein 1 (XBP1) as well as ATF6 activation, induce the expression of chaperones and UPR components. Finally, long-term ER stress can induce autophagy through the PERK-mediated induction of ATF4, which can promote the expression of key autophagy-related proteins, which are needed for autophagosome formation. P, phosphate; Ub, ubiquitin.
Baiceanu, A. et al. (2016) Endoplasmic reticulum proteostasis in hepatic steatosis
Nat. Rev. Endocrinol. doi: /nrendo