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.
- 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: [email protected].
- 12. Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
- 13. Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
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.