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

• DOI: 10.1016/j.cmet.2023.05.011
• Publication Date: 2023-06-20T15:02:06Z
• Authors: Xinliang Lu; Xianghui Kong; Hao Wu; Jiayue Hao; Sirui Li; Zichun Gu; Xianchang Zeng; Yingying Shen; Shibo Wang; Jiming Chen; Xuefeng Fei; Yi Sun; Xu Li; Lingling Jiang; Fei Yang; Jianli Wang; Zhijian Cai
• Keywords: 2. Zero hunger; Inflammation; Mice; Metabolic Diseases; Ubiquitin-Protein Ligases; Ubiquitination; Animals; Obesity

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.