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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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