2. Academic Validation
  3. UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders

UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders

  • Cell Metab. 2023 Jun 14;S1550-4131(23)00209-7. doi: 10.1016/j.cmet.2023.05.011.
Xinliang Lu 1,  Xianghui Kong 2,  Hao Wu 3,  Jiayue Hao 2,  Sirui Li 4,  Zichun Gu 5,  Xianchang Zeng 2,  Yingying Shen 6,  Shibo Wang 2,  Jiming Chen 2,  Xuefeng Fei 7,  Yi Sun 8,  Xu Li 9,  Lingling Jiang 10,  Fei Yang 11,  Jianli Wang 12,  Zhijian Cai 13
Affiliations

Affiliations

  • 1 Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 2 Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 3 Gastroenterology, Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325000, China.
  • 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5 Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
  • 6 Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310020, China.
  • 7 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 8 Cancer Institute of the Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
  • 9 School of Life Science, Westlake University, Hangzhou 310024, China.
  • 10 Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
  • 11 Chronic Disease Research Institute, The Children's Hospital, National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: yangfei919@zju.edu.cn.
  • 12 Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: jlwang@zju.edu.cn.
  • 13 Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: caizj@zju.edu.cn.
PMID: 37343564 DOI: 10.1016/j.cmet.2023.05.011
Abstract

Inflammation is closely associated with obesity and related metabolic disorders. However, its origin during obesity is largely unknown. Here, we report that ubiquitin-conjugating Enzyme E2M (UBE2M) is critical to obesity-related inflammation induced by macrophages. In mice with UBE2M-deficient macrophages, obesity, Insulin resistance, and hepatic steatosis induced by a high-fat diet are greatly alleviated, an effect related to the decreased proinflammatory activity of macrophages due to reduced IL-1β production. Mechanistically, UBE2M deficiency inhibits the neddylation of E3 ubiquitin Ligase TRIM21 on K129/134, leading to reduced recruitment and ubiquitination-mediated degradation of E3 ubiquitin Ligase VHL. Subsequently, VHL reduces HIF-1α-induced IL-1β production by degrading HIF-1α. Targeting macrophage TRIM21 with Trim21 antisense oligonucleotide-loaded red blood cell extracellular vesicles effectively inhibits obesity-induced inflammation and related metabolic disorders. Thus, our results demonstrate that macrophage UBE2M is essential for obesity-induced inflammation and that TRIM21 is a proof-of-concept target for treating obesity and associated metabolic diseases.

Keywords

TRIM21; UBE2M; inflammation; neddylation; obesity.

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