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Nat Cell Biol. 2015 Dec;17(12):1546-55. doi: 10.1038/ncb3266. Epub 2015 Nov 9.

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

Author information

1
Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853, USA.
2
Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
3
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
4
Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905, USA.
5
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
6
Department of Pathology, Northwestern University, Chicago, Illinois 60611, USA.
7
Department of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA.
8
Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.
9
Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.
10
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
11
Education and Research Support Center, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
12
Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
13
Nutrition Metabolism and Genomics group, Wageningen University, Bomenweg 2, 6703HD Wageningen, The Netherlands.
14
Laboratory Animal Research Center, Medical College of Soochow University, Suzhou 215006, Jiangsu, China.
15
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
16
Department of Clinical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.

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.

PMID:
26551274
PMCID:
PMC4670240
DOI:
10.1038/ncb3266
[Indexed for MEDLINE]
Free PMC Article

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