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(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.
authors.affiliation: Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Shengyi
authors.initials: S
authors.lastname: Sun
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Shi
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Sha
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Shu
authors.affiliation: Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905, USA.
authors.forename: Hongming
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Pathology, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Beixue
authors.initials: B
authors.lastname: Gao
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA.|Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Bu
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Guber
authors.affiliation: Department of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA.|Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.|Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.
authors.forename: Xiling
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
authors.affiliation: Education and Research Support Center, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: Department of Pathology, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Billy
authors.initials: B
authors.lastname: Tsai
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: John R
authors.identifier: http://orcid.org/0000-0001-5267-1672
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas 79905, USA.
authors.forename: Haoquan
authors.initials: H
authors.lastname: Wu
authors.affiliation: Nutrition Metabolism and Genomics group, Wageningen University, Bomenweg 2, 6703HD Wageningen, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.affiliation: Laboratory Animal Research Center, Medical College of Soochow University, Suzhou 215006, Jiangsu, China.
authors.forename: Qiaoming
authors.initials: Q
authors.lastname: Long
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Duhamel
authors.affiliation: Department of Clinical Science, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Simpson
authors.affiliation: Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853, USA.|Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D009363:Neoplasm Proteins; C561422:OS9 protein, mouse; D011506:Proteins; C492169:Sel1h protein, mouse; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases