Fig. 2. Regulation of the UPR and its pathways. The UPR is regulated by three ER stress sensors: PERK, ATF6, and IRE1. Normally, these sensors are inactivated in the ER due to their associations with BiP. UPR activation occurs when BiP dissociates from the ER stress transducers, triggered by high levels of unfolded or misfolded proteins. The pathways are as follows: PERK Pathway: Following BiP dissociation, PERK becomes active through oligomerization and autophosphorylation. p-PERK then phosphorylates eIF2α, reducing ER load by decreasing global protein synthesis. p-eIF2α also preferentially stimulates the translation of ATF4, enhancing the expression of cytoprotective genes, autophagy-related genes, and ERAD-related genes. IRE1 Pathway: IRE1 becomes active after BiP dissociation through oligomerization and autophosphorylation. p-IRE1 splices XBP1 mRNA to generate XBP1s, a transcription factor that stimulates the expression of chaperones and genes involved in ER expansion, ERAD, autophagy, and cytoprotection. p-IRE1 also reduces ER load through mRNA degradation via RIDD. ATF6 Pathway: After BiP dissociation, ATF6 translocates to the Golgi complex, where it is cleaved by the proteases S1P and S2P. ATF6p50 then migrates to the nucleus, stimulating the expression of chaperones, autophagy-related genes, ERAD-related genes, and cytoprotective genes.
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