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

Cell Metab. 2023 Aug 8;35(8):1390-1405.e8. doi: 10.1016/j.cmet.2023.05.011. Epub 2023 Jun 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Inflammation
  • Metabolic Diseases* / etiology
  • Mice
  • Obesity / complications
  • Obesity / metabolism
  • Ubiquitin-Protein Ligases* / metabolism
  • Ubiquitination

Substances

  • Ubiquitin-Protein Ligases