Ubiquitination of Inositol-requiring Enzyme 1 (IRE1) by the E3 Ligase CHIP Mediates the IRE1/TRAF2/JNK Pathway |
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| Authors: | Xu Zhu Ju Zhang Huiying Sun Cuicui Jiang Yusheng Dong Qiang Shan Siyuan Su Yingying Xie Ningzhi Xu Xiaomin Lou Siqi Liu |
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| Institution: | From the ‡Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.;the §University of Chinese Academy of Sciences, Beijing 100049, China.;¶Beijing Protein Innovation, Beijing 101318, China, and ;the ‖Laboratory of Cell and Molecular Biology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China |
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| 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, Lys545 and Lys828, were targeted for Lys63-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 Lys545 and Lys828, 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. |
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| Keywords: | ER Stress Senescence Signal Transduction Ubiquitin Ligase Unfolded Protein Response (UPR) CHIP IRE1 |
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