Department of Biotechnology, University of Kashmir, Hazratbal J&K, India.
Department of Computational and Data Science (CDS), Indian Institute of Science (IISc), Bengaluru, India.
FEBS Lett. 2023 Apr;597(7):962-974. doi: 10.1002/1873-3468.14593. Epub 2023 Feb 16.
IRE1 is a transmembrane signalling protein that activates the unfolded protein response under endoplasmic reticulum stress. IRE1 is endowed with kinase and endoribonuclease activities. The ribonuclease activity of IRE1 can switch substrate specificities to carry out atypical splicing of Xbp1 mRNA or trigger the degradation of specific mRNAs. The mechanisms regulating the distinct ribonuclease activities of IRE1 have yet to be fully understood. Here, we report the Bcl-2 family protein Bid as a novel recruit of the IRE1 complex, which directly interacts with the cytoplasmic domain of IRE1. Bid binding to IRE1 leads to a decrease in IRE1 phosphorylation in a way that it can only perform Xbp1 splicing while mRNA degradation activity is repressed. The RNase outputs of IRE1 have been found to regulate the homeostatic-apoptotic switch. This study, thus, provides insight into IRE1-mediated cell survival.
IRE1 是一种跨膜信号蛋白，在内质网应激下激活未折叠蛋白反应。IRE1 具有激酶和内切核酸酶活性。IRE1 的核糖核酸酶活性可以切换底物特异性，对 Xbp1 mRNA 进行非典型剪接，或触发特定 mRNA 的降解。调节 IRE1 不同核糖核酸酶活性的机制尚未完全理解。在这里，我们报告 Bcl-2 家族蛋白 Bid 作为 IRE1 复合物的一种新的募集物，它直接与 IRE1 的细胞质结构域相互作用。Bid 与 IRE1 的结合导致 IRE1 磷酸化减少，从而只能进行 Xbp1 剪接，而 mRNA 降解活性受到抑制。IRE1 的核糖核酸酶产物已被发现调节体内平衡-凋亡开关。因此，本研究为 IRE1 介导的细胞存活提供了新的见解。
