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. Yates; Haoquan Wu; Sander Kersten; Qiaoming Long; Gerald E. Duhamel; Kenneth W. Simpson; Ling Qi

doi:10.1038/ncb3266

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^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

188 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 language	English (US)
Pages (from-to)	1546-1555
Number of pages	10
Journal	Nature Cell Biology
Volume	17
Issue number	12
DOIs	https://doi.org/10.1038/ncb3266
State	Published - Nov 27 2015

Funding

We thank K.-L. Tung for help with the organoid culture; and other members of the Qi laboratory for comments and technical assistance. S.S. is an International Student Research Fellow of the Howard Hughes Medical Institute (59107338). L.Q. is the recipient of the Junior Faculty and Career Development Awards from American Diabetes Association (ADA). This work was supported by R21AI085332 (G.E.D.), 1R03AI114344 (H.W.), Chinese National Natural Science Foundation Grant 31371391 (Q.L.), National Heart, Lung, and Blood Institute Proteomics Center Award HHSN268201000035C, R01 MH067880 and 8P41GM103533-17 (J.R.Y. III), NIH R01DK105393, R01GM113188, UL1TR000457 of the Clinical and Translation Science Center at Weill Cornell Medical College, ADA 1-12-CD-04 and Cornell VERG seed grant (L.Q.).

ASJC Scopus subject areas

Cell Biology

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@article{275bb45bfbdb4b909bcdc35c72ce5242,

title = "IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = nov,

day = "27",

doi = "10.1038/ncb3266",

language = "English (US)",

volume = "17",

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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, RD, Shen, X, Lee, AH, Iwawaki, T, Paton, AW, Paton, JC, Fang, D, Tsai, B, Yates, JR, Wu, H, Kersten, S, Long, Q, Duhamel, GE, Simpson, KW & Qi, L 2015, 'IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation', Nature Cell Biology, vol. 17, no. 12, pp. 1546-1555. https://doi.org/10.1038/ncb3266

TY - JOUR

T1 - IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation

AU - Sun, Shengyi

AU - Shi, Guojun

AU - Sha, Haibo

AU - Ji, Yewei

AU - Han, Xuemei

AU - Shu, Xin

AU - Ma, Hongming

AU - Inoue, Takamasa

AU - Gao, Beixue

AU - Kim, Hana

AU - Bu, Pengcheng

AU - Guber, Robert D.

AU - Shen, Xiling

AU - Lee, Ann Hwee

AU - Iwawaki, Takao

AU - Paton, Adrienne W.

AU - Paton, James C.

AU - Fang, Deyu

AU - Tsai, Billy

AU - Yates, John R.

AU - Wu, Haoquan

AU - Kersten, Sander

AU - Long, Qiaoming

AU - Duhamel, Gerald E.

AU - Simpson, Kenneth W.

AU - Qi, Ling

PY - 2015/11/27

Y1 - 2015/11/27

N2 - 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.

AB - 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.

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U2 - 10.1038/ncb3266

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M3 - Article

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AN - SCOPUS:84948712979

SN - 1465-7392

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EP - 1555

JO - Nature Cell Biology

JF - Nature Cell Biology

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ER -

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

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