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

作     者：Wanxin Zhuang Lei Zhang Yi Zheng Bingyu Liu Chunhong Ma Wei Zhao Suxia Liu Feng Liu Chengjiang Gao 

作者机构：Key Laboratory of Infection and Immunity of Shandong Province&Key Laboratory for Experimental Teratology of Ministry of EducationShandong UniversityJinanShandong250012PR China Department of ImmunologySchool of Biomedical SciencesShandong UniversityJinanShandong250012PR China 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2022年第19卷第10期

页      面：1141-1152页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学] 

基　　金：This work was supported by grants from the National Key Research and Development Program(2021YFC2300603),the National Natural Science Foundation of China(32000633,31730026,81930039) the Natural Science Foundation of Shandong Province(ZR2020QH136) the China Postdoctoral Science Foundation(2020M682187) the Postdoctoral Innovation Project of Shandong Province(202002012). 

主　　题：ASC inflammasome K48-linked ubiquitination proteasomal degradation USP3 

摘      要：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.