Cell Mol Immunol . 2022 Sep 1. (IF:22.096).

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

Wanxin Zhuang 1 2Lei Zhang 1 2Yi Zheng 1 2Bingyu Liu 1 2Chunhong Ma 1 2Wei Zhao 1 3Suxia Liu 1 2Feng Liu 4 5Chengjiang Gao 6 7

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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.