IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation
IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation
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IRE1alpha 是内质网相关降解的内源性底物。
DOI：
10.1038/ncb3266
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发表时间：
2015-12-01
影响因子：
21.3
通讯作者：
Qi, Ling
中科院分区：
文献类型：
--
作者：
Sun, Shengyi;Shi, Guojun;Qi, Ling
内质网（ER）相关降解（ERAD）是清除内质网中错误折叠蛋白的主要质量控制机制；然而，其生理意义和内源性ERAD底物的性质在很大程度上仍未被探索。在这里，我们发现IRE1 α，未折叠蛋白反应（UPR）的传感器，是Sel1L-Hrdl ERAD复合物的真正底物。erad介导的IRE1 α降解在基础条件下以bip依赖的方式发生，需要IRE1 α的膜内亲水性残基和凝集素蛋白OS9，并且被内质网胁迫减弱。ERAD缺乏导致体内和体外IRE1 α蛋白稳定、积累和轻度激活。虽然肠细胞特异性sel1l敲除小鼠（Se/1L(Delta IEC)）是活的，看起来正常，但它们非常容易发生实验性结肠炎和炎症相关的生态失调，以IRE1 α依赖但chop独立的方式。因此，Sel1L-Hrdl ERAD通过管理体内IRE1 α信号的蛋白质周转，在抑制IRE1 α信号方面发挥着独特的重要作用。
Endoplasmic reticulum (ER)-associated degradation (ERAD) represents a principle quality control mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unexplored. Here we discover that IRE1 alpha, the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrdl ERAD complex. ERAD-mediated IRE1 alpha degradation occurs under basal conditions in a BiP-dependent manner, requires both the intramembrane hydrophilic residues of IRE1 alpha and the lectin protein OS9, and is attenuated by ER stress. ERAD deficiency causes IRE1 alpha protein stabilization, accumulation and mild activation both in vitro and in vivo. Although enterocyte-specific Sel1L-knockout mice (Se/1L(Delta IEC)) are viable and seem normal, they are highly susceptible to experimental colitis and inflammation-associated dysbiosis, in an IRE1 alpha-dependent but CHOP-independent manner. Hence, Sel1L-Hrdl ERAD serves a distinct, essential function in restraint of IRE1 alpha signalling in vivo by managing its protein turnover.