Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/98669
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Type: Journal article
Title: IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation
Other Titles: IRE1alpha is an endogenous substrate of endoplasmic-reticulum-associated degradation
Author: Sun, S.
Shi, G.
Sha, H.
Ji, Y.
Han, X.
Shu, X.
Ma, H.
Inoue, T.
Gao, B.
Kim, H.
Bu, P.
Guber, R.
Shen, X.
Lee, A.
Iwawaki, T.
Paton, A.
Paton, J.
Fang, D.
Tsai, B.
Yates, J.
et al.
Citation: Nature Cell Biology, 2015; 17(12):1546-1555
Publisher: Nature Publishing Group
Issue Date: 2015
ISSN: 1465-7392
1476-4679
Statement of
Responsibility: 
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. Yates III, Haoquan Wu, Sander Kersten, Qiaoming Long, Gerald E. Duhamel, Kenneth W. Simpson & Ling Qi
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(ΔIEC)) 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.
Keywords: Enterocytes
Gene Expression Profiling
Reverse Transcriptase Polymerase Chain Reaction
Unfolded Protein Response
HEK293 Cells
Endoplasmic Reticulum-Associated Degradation
Rights: © 2015 Macmillan Publishers Limited. All rights reserved.
DOI: 10.1038/ncb3266
Grant ID: 59107338
R21AI085332
1R03AI114344
Published version: http://dx.doi.org/10.1038/ncb3266
Appears in Collections:Aurora harvest 3
Microbiology and Immunology publications

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