USP3 deubiquitinates and stabilizes the adapter protein ASC to regulate inflammasome activation

  • Cell Mol Immunol. 2022 Oct;19(10):1141-1152. doi: 10.1038/s41423-022-00917-7.
Wanxin Zhuang  1  2 ,  Lei Zhang  1  2 ,  Yi Zheng  1  2 ,  Bingyu Liu  1  2 ,  Chunhong Ma  1  2 ,  Wei Zhao  1  3 ,  Suxia Liu  1  2 ,  Feng Liu  4  5 ,  Chengjiang Gao  6  7
Affiliations
  • 1. Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, PR China.
  • 2. Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, 250012, PR China.
  • 3. Department of Pathogenic Biology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, 250012, PR China.
  • 4. Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, PR China. [email protected].
  • 5. Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, 250012, PR China. [email protected].
  • 6. Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, PR China. [email protected].
  • 7. Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, 250012, PR China. [email protected].
PMID: 36050480 DOI: 10.1038/s41423-022-00917-7
Abstract

Inflammasomes are essential components of the innate immune system and its defense against infections, whereas the dysregulation of inflammasome activation has a detrimental effect on human health. The activation of inflammasomes is subjected to tight regulation to maintain immune homeostasis, yet the underlying mechanism remains elusive. Here, we identify USP3 as a direct deubiquitinating enzyme (DUB) for ASC, the central adapter mediating the assembly and activation of most inflammasomes. USP3 removes the K48-linked ubiquitination on ASC and strengthens its stability by blocking proteasomal degradation. Additionally, USP3 promotes inflammasome activation, and this function was confirmed in mouse models of aluminum (Alum)-induced Peritonitis, F. novicida Infection and flagellin-induced Pneumonia in vivo. Our work unveils that USP3 functions as a key regulator of ASC ubiquitination and maintains the physiological role of ASC in mediating inflammasome activation, and we propose a new mechanism by which the ubiquitination of ASC regulates inflammasome activation.

Keywords
ASC; K48-linked ubiquitination; USP3; inflammasome; proteasomal degradation.