Figure 2 The unfolded protein response

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Figure 2 The unfolded protein response Figure 2 | The unfolded protein response. The unfolded protein response (UPR) starts with the activation of 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), following the removal of the chaperone binding immunoglobulin protein (BiP). PERK phosphorylates and inactivates the eukaryotic translation initiation factor 2α (eIF2α), leading to a general decrease in protein translation except for cyclic AMP-dependent transcription factor ATF-4 (ATF4), which induces the expression of factors involved in antioxidant defence, amino acid metabolism, autophagy and apoptosis, such as DNA damage-inducible transcript 3 protein (C/EBP homologous protein; CHOP) and tribbles homologue 3 (TRB3). ATF4 also induces the expression of protein phosphatase 1 regulatory subunit 15A (also known as growth arrest and DNA damage-inducible protein; GADD34), a regulatory subunit of serine/threonine-protein phosphatase PP1γ catalytic subunit (PP1G). GADD34 expression enables the dephosphorylation of eIF2α and the reinitiation of translation. Activated PERK also phosphorylates nuclear-factor-erythroid-2-related factor 2 (NFE2-related factor 2, also known as NRF2), which positively affects antioxidant defence. Once activated, IRE1 promotes the splicing of XBP1 mRNA, which is then translated into the active X-box-binding protein 1 (XBP1), which transactivates the expression of components related to protein folding, ER-associated protein degradation (ERAD) and protein quality control. IRE1 also promotes the degradation of RNAs localized in the ER vicinity by regulated IRE1-dependent decay (RIDD), which induces caspase-2 and thioredoxin-interacting protein (TXNIP) expression. In addition, IRE1 activates the c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase kinase 5 (also known as apoptosis signal-regulating kinase 1; ASK1) pathway through the binding of tumour necrosis factor (TNF) receptor-associated factor 2 (TRAF2). Finally the inactive precursor of ATF6 is transferred to the Golgi apparatus where it is cleaved by membrane-bound site-1 (S1P) and site-2 (S2P) proteases into an active form, which induces the expression of chaperones and UPR components. P, phosphate. Baiceanu, A. et al. (2016) Endoplasmic reticulum proteostasis in hepatic steatosis Nat. Rev. Endocrinol. doi:10.1038/nrendo.2016.124