USP22 suppresses the NLRP3 inflammasome by degrading NLRP3 via ATG5-dependent autophagy

Autophagy. 2023 Mar;19(3):873-885. doi: 10.1080/15548627.2022.2107314. Epub 2022 Aug 8.

Abstract

The NLRP3 inflammasome is involved in a diverse range of inflammatory diseases. The activation of inflammasomes must be tightly regulated to prevent excessive inflammation, and the protein ubiquitination system is reported to be one of the ways in which inflammasome activation is regulated. However, the deubiquitination regulatory mechanisms of inflammasome activation remain elusive. Here, we demonstrated that USP22 (ubiquitin specific peptidase 22) promotes NLRP3 degradation and inhibits NLRP3 inflammasome activation. USP22 deficiency or in vivo silencing significantly increases alum-induced peritonitis and lipopolysaccharide-induced systemic inflammation. Mechanistically, USP22 inhibits NLRP3 inflammasome activation via the promotion of ATG5-mediated macroautophagy/autophagy. USP22 stabilizes ATG5 via decreasing K27- and K48-linked ubiquitination of ATG5 at the Lys118 site. Taken together, these findings reveal the role USP22 plays in the regulation of NLRP3 inflammasome activation and suggest a potential therapeutic target to treat NLRP3 inflammasome-related diseases.Abbreviations: ATG5: autophagy related 5; ATP: adenosine triphosphate; CASP1: caspase 1; IL18: interleukin 18; IL1B/IL-1β: interleukin 1 beta; LPS: lipopolysaccharide; NLRC4: NLR family, CARD domain containing 4; NLRP3: NLR family, pyrin domain containing 3; PYCARD/ASC: PYD and CARD domain containing; TNF/TNF-α: tumor necrosis factor; USP22: ubiquitin specific peptidase 22.

Keywords: Autophagy; NLRP3; autophagy related 5; inflammasome; ubiquitin specific peptidase 22.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Autophagy-Related Protein 5
  • Caspase 1 / metabolism
  • Humans
  • Inflammasomes* / metabolism
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Lipopolysaccharides
  • Caspase 1
  • Ubiquitin-Specific Proteases
  • Interleukin-1beta
  • ATG5 protein, human
  • Autophagy-Related Protein 5
  • Usp22 protein, human
  • Ubiquitin Thiolesterase
  • Nlrp3 protein, mouse
  • Atg5 protein, mouse

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 32000668, U1801283, 31870908, 32100700), the Guangdong Province Basic and Applied Basic Research Fund (No. 2019A1515110146), the Guangdong Provincial Science and Technology Program (No. 2019B030301009) and SZU Top Ranking Project (No. 86000000210) to Weilin Chen; Guangdong Science and Technology Department; Basic and Applied Basic Research Foundation of Guangdong Province; Shenzhen University.