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

• Published in: Nature cell biology Vol. 17; no. 12; pp. 1546 - 1555
• Main Authors: Sun, Shengyi, Shi, Guojun, Sha, Haibo, Ji, Yewei, Han, Xuemei, Shu, Xin, Ma, Hongming, Inoue, Takamasa, Gao, Beixue, Kim, Hana, Bu, Pengcheng, Guber, Robert D, Shen, Xiling, Lee, Ann-Hwee, Iwawaki, Takao, Paton, Adrienne W, Paton, James C, Fang, Deyu, Tsai, Billy, Yates, 3rd, John R, Wu, Haoquan, Kersten, Sander, Long, Qiaoming, Duhamel, Gerald E, Simpson, Kenneth W, Qi, Ling
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2015
• Subjects: Animals; Base Sequence; Blotting, Western; Cells, Cultured; Cellular control mechanisms; Chair Nutrition Metabolism and Genomics; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum-Associated Degradation - genetics; Endoribonucleases - genetics; Endoribonucleases - metabolism; Enterocytes - metabolism; Female; Gene Expression Profiling; Genetic aspects; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HEK293 Cells; HNE Nutrition, Metabolism and Genomics; HNE Voeding, Metabolisme en Genomics; Humans; Lectins - genetics; Lectins - metabolism; Male; Mice; Mice, Knockout; Mice, Transgenic; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nutrition, Metabolism and Genomics; Observations; Oligonucleotide Array Sequence Analysis; Properties; Protein folding; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins - genetics; Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Unfolded Protein Response - genetics; VLAG; Voeding, Metabolisme en Genomica
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3266

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.