IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation

Shengyi Sun, Guojun Shi, Haibo Sha, Yewei Ji, Xuemei Han, Xin Shu, Hongming Ma, Takamasa Inoue, Beixue Gao, Hana Kim, Pengcheng Bu, Robert D. Guber, Xiling Shen, Ann Hwee Lee, Takao Iwawaki, Adrienne W. Paton, James C. Paton, Deyu Fang, Billy Tsai, John R. YatesHaoquan Wu, Sander Kersten, Qiaoming Long, Gerald E. Duhamel, Kenneth W. Simpson, Ling Qi

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

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 IRE1α, the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. ERAD-mediated IRE1α degradation occurs under basal conditions in a BiP-dependent manner, requires both the intramembrane hydrophilic residues of IRE1α and the lectin protein OS9, and is attenuated by ER stress. ERAD deficiency causes IRE1α protein stabilization, accumulation and mild activation both in vitro and in vivo. Although enterocyte-specific Sel1L-knockout mice (Sel1L IEC) are viable and seem normal, they are highly susceptible to experimental colitis and inflammation-associated dysbiosis, in an IRE1α-dependent but CHOP-independent manner. Hence, Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1α signalling in vivo by managing its protein turnover.

Original languageEnglish
Pages (from-to)1546-1555
Number of pages10
JournalNature Cell Biology
Volume17
Issue number12
DOIs
StatePublished - Nov 27 2015
Externally publishedYes

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    Sun, S., Shi, G., Sha, H., Ji, Y., Han, X., Shu, X., Ma, H., Inoue, T., Gao, B., Kim, H., Bu, P., Guber, R. D., Shen, X., Lee, A. H., Iwawaki, T., Paton, A. W., Paton, J. C., Fang, D., Tsai, B., ... Qi, L. (2015). IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nature Cell Biology, 17(12), 1546-1555. https://doi.org/10.1038/ncb3266