摘要
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.
摘要译文
哺乳动物肌醇需要酶1α（IRE1α）是所有内质网（ER）应激传感器中最保守的，其包括激活转录因子（ATF）6和双链RNA依赖性蛋白激酶（PKR）样ER激酶（PERK） ）。已知IRE1α剪接X-box结合蛋白1（XBP1）mRNA，其在ER应激下由ATF6诱导。该剪接的XBP1 mRNA被翻译成活性转录因子，其促进特定基因的表达以减轻ER应激。在本文中，我们报道除了ATF6诱导XBP1表达外，在ER应激下，IRE1α表达由PERF下游的ATF4诱导。 IRE1α表达增加导致XBP1 mRNA的剪接比率更高。这种效应不是短暂的，并且不仅影响该途径的激活状态的强度而且影响该途径的持续时间。这些多种调节机制可以调节对各种水平或类型的ER应激的反应。
Akio Tsuru[1];Yasutaka Imai[1];Michiko Saito[1];Kenji Kohno[1]. Novel mechanism of enhancing IRE1α-XBP1 signalling via the PERK-ATF4 pathway[J]. Scientific reports, 2016