Fig. 1

Summary of UPR signaling pathway. Under homeostatic conditions, PERK, IRE1, and ATF6 bind to immunoglobulin binding protein (Bip), inhibiting their activity. During ER stress, Bip dissociates, and PERK, IRE1, and ATF6 become activated. PERK dimerises and phosphorylates eIF2α, impeding the assembly of 80 S ribosomes, resulting in the inhibition of protein translation. Additionally, eIF2α induces the translation of activating transcription factor 4 (ATF4) and activates enhancer-binding protein C/EBP homologous protein (CHOP) expression, culminating in the induction of apoptosis. Activated IRE1 dimerises and triggers its endonuclease activity, leading to the degradation of mRNA in the ER and a consequent reduction in protein biosynthesis. Simultaneously, IRE1 cleaves the transcript encoding X box-binding protein 1 (XBP1), inducing endoplasmic reticulum-associated degradation (ERAD) gene expression, accelerating protein folding, and facilitating the degradation of misfolded proteins. ATF6 translocates to the Golgi, where it undergoes cleavage and activation by the S1 and S2 proteases, thereby activating the transcription of UPR target genes. (ER stress, endoplasmic reticulum stress; UPR, unfolded protein response; PERK, protein kinase R-like endoplasmic reticulum kinase; IRE1, inositol-requiring enzyme 1; ATF6, activating transcription factor 6; ATF4, activating transcription factor 4; Bip, immunoglobulin binding protein; eIF2α, eukaryotic initiation factor 2α; CHOP, enhancer-binding protein C/EBP homologous protein; XBP1, X box-binding protein 1; ERAD, endoplasmic reticulum-associated degradation.)