SUMOylation of ERp44 enhances Ero1α ER retention contributing to the pathogenesis of obesity and insulin resistance

Hao Xie; Yu-Han Wang; Xin Liu; Jia Gao; Chunliang Yang; Teng Huang; Lu Zhang; Xi Luo; Zhichao Gao; Ting Wang; Tong Yan; Yanjun Liu; Ping Yang; Qilin Yu; Shiwei Liu; Yi Wang; Fei Xiong; Shu Zhang; Qing Zhou; Cong-Yi Wang

doi:10.1016/j.metabol.2022.155351

SUMOylation of ERp44 enhances Ero1α ER retention contributing to the pathogenesis of obesity and insulin resistance

Metabolism. 2023 Feb:139:155351. doi: 10.1016/j.metabol.2022.155351. Epub 2022 Nov 22.

Authors

Hao Xie¹, Yu-Han Wang¹, Xin Liu², Jia Gao¹, Chunliang Yang¹, Teng Huang¹, Lu Zhang³, Xi Luo¹, Zhichao Gao¹, Ting Wang¹, Tong Yan⁴, Yanjun Liu⁴, Ping Yang¹, Qilin Yu¹, Shiwei Liu⁵, Yi Wang¹, Fei Xiong¹, Shu Zhang⁶, Qing Zhou⁷, Cong-Yi Wang⁸

Affiliations

¹ Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Interventional Radiology, Renmin Hospital of Wuhan University, Wuhan, China.
³ Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ The Center for Obesity and Metabolic Health, Affiliated Hospital of Southwest Jiaotong University, the Third People's Hospital of Chengdu, 82 Qinglong Road, Chengdu 610031, Sichuan, China.
⁵ Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University. Taiyuan, China.
⁶ Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: szhang@tjh.tjmu.edu.cn.
⁷ Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: zhouqing@tjh.tjmu.edu.cn.
⁸ Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: wangcy@tjh.tjmu.edu.cn.

PMID: 36427672
DOI: 10.1016/j.metabol.2022.155351

Abstract

Objective: As the only E2 conjugating enzyme for the SUMO system, Ubc9-mediated SUMOylation has been recognized to regulate diverse biological processes, but its impact on adipocytes relevant to obesity and insulin resistance is yet to be elucidated.

Methods: We established adipocyte-specific Ubc9 deficient mice to explore the effects of Ubc9 on obesity and metabolic disorders induced by high-fat diet (HFD) in adult mice. The molecular targets of SUMOylation were explored by liquid chromatography-mass spectrometry, and the regulatory mechanism of SUMOylation in T2D was analyzed.

Results: Adipocyte-specific depletion of Ubc9 (AdipoQ-Cre-Ubc9^fl/fl, Ubc9^AKO) protected mice from HFD-induced obesity, insulin resistance, and hepatosteatosis. The Ubc9^AKO mice were featured by the reduced HFD-induced endoplasmic reticulum (ER) stress and inflammatory response. Mechanically, over nutrition rendered adipocytes to undergo a SUMOylation turnover characterized by the change of SUMOylation levels and substrates. ERp44 displayed the highest change in terms of SUMOylation levels of substrates involved in ER-related functions. The lack of ERp44 SUMOylation at lysine 76 (K76) located within the thioredoxin (TRX)-like domain by Ubc9 deficiency enhanced its degradation and suppressed its covalent binding to Ero1α, an oxidase that exists in the ER but lacks ER retention motif, thereby alleviating endoplasmic reticulum stress by promoting Ero1α secretion.

Conclusions: Our data suggest that modulation of ERp44 SUMOylation in adipocytes could be a feasible strategy against obesity and insulin resistance in clinical settings.

Keywords: Adipocyte; ER stress; Insulin resistance; Obesity; SUMOylation; Ubc9.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Insulin Resistance*
Membrane Proteins
Mice
Molecular Chaperones
Sumoylation*

Substances

ERp44 protein, mouse
Membrane Proteins
Molecular Chaperones