Abstract
Mammalian inositol-requiring enzyme 1α (IRE1α) is the most conserved of all endoplasmic reticulum (ER) stress sensors, which includes activating transcription factor (ATF) 6 and double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK). IRE1α has been known to splice X-box binding protein 1 (XBP1) mRNA, which is induced by ATF6 under ER stress. This spliced XBP1 mRNA is translated into the active transcription factor that promotes the expression of specific genes to alleviate ER stress. Herein, we report that in addition to the induction of XBP1 expression by ATF6, IRE1α expression is induced by ATF4, which is downstream of PERK, under ER stress. Increased IRE1α expression results in a higher splicing ratio of XBP1 mRNA. This effect was not transient and affected not only the intensity but also the duration of the activated state of this pathway. These multiple regulatory mechanisms may modulate the response to various levels or types of ER stress.
Highlights
Three principal branches of the UPR have been identified, signalling in which is initiated by the transmembrane stress sensors–activating transcription factor (ATF) 6, inositol-requiring enzyme 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like endoplasmic reticulum (ER) kinase (PERK), respectively
12 h after injection, while total eukaryotic initiation factor 2α (eIF2α) remained constant. These results indicate that tunicamycin induced ER stress in the mouse liver since induction of Chop, and phosphorylation of eIF2α are well-known ER-stress markers
It is well known that activated ATF6 induces the transcription of XBP116,22 and of other UPR target genes
Summary
Three principal branches of the UPR have been identified, signalling in which is initiated by the transmembrane stress sensors–activating transcription factor (ATF) 6, inositol-requiring enzyme 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK), respectively. ATF6 is originally expressed as a type II transmembrane protein, but under ER stress, its cytosolic amino terminal segment is released by proteolysis and functions as a transcription factor that induces UPR target genes including those encoding chaperones and other transcription factors such as X-box binding protein 1 (XBP1). During ER stress, PERK phosphorylates eukaryotic initiation factor 2α (eIF2α ), which attenuates general translation but induces the selective translation of ATF4 that up-regulates UPR target genes[20,21]. We revealed that the increase in IRE1α expression depended on PERK-ATF4 pathway. PERK knockout decreased the ratio of XBP1 mRNA splicing These findings indicated that PERK-ATF4 pathway affected the efficiency of XBP1 mRNA splicing by regulating IRE1α expression
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