title: Ubiquitination of inositol-requiring enzyme 1 (IRE1) by the E3 ligase CHIP mediates the IRE1/TRAF2/JNK pathway.
abstract: Deciphering the inositol-requiring enzyme 1 (IRE1) signaling pathway is fundamentally important for understanding the unfolded protein response (UPR). The ubiquitination of proteins residing on the endoplasmic reticulum (ER) membrane has been reported to be involved in the UPR, although the mechanism has yet to be fully elucidated. Using immunoprecipitation and mass spectrometry, IRE1 was identified as a substrate of the E3 ligase CHIP (carboxyl terminus of HSC70-interacting protein) in HEK293 cells under geldanamycin-induced ER stress. Two residues of IRE1, Lys(545) and Lys(828), were targeted for Lys(63)-linked ubiquitination. Moreover, in CHIP knockdown cells, IRE1 phosphorylation and the IRE1-TRAF2 interaction were nearly abolished under ER stress, which may be due to lacking ubiquitination of IRE1 on Lys(545) and Lys(828), respectively. The cellular responses were evaluated, and the data indicated that CHIP-regulated IRE1/TRAF2/JNK signaling antagonized the senescence process. Therefore, our findings suggest that CHIP-mediated ubiquitination of IRE1 contributes to the dynamic regulation of the UPR.
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China,; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Sun
authors.affiliation: Beijing Protein Innovation, Beijing 101318, China, and.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Beijing Protein Innovation, Beijing 101318, China, and.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shan
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China,; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Su
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China,; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Laboratory of Cell and Molecular Biology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Ningzhi
authors.initials: N
authors.lastname: Xu
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China,. Electronic address: louxm@big.ac.cn.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Lou
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China,; University of Chinese Academy of Sciences, Beijing 100049, China,. Electronic address: siqiliu@big.ac.cn.
authors.forename: Siqi
authors.initials: S
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D016922:Cellular Senescence; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination; D056811:Unfolded Protein Response
chemical_list: D047992:TNF Receptor-Associated Factor 2; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases
keywords: CHIP; ER Stress; IRE1; Senescence; Signal Transduction; Ubiquitin Ligase; Unfolded Protein Response (UPR)