USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D  

作　　者：Liqiu Wang Mengqiu Li Guangyu Lian Shuai Yang Yaoxing Wu Jun Cui 

机构地区：[1]MOE Key Laboratory of Gene Function and Regulation,Guangdong Province Key Laboratory of Pharmaceutical Functional Genes,State Key Laboratory of Biocontrol,School of Life Sciences of Sun Yat-sen University,Guangzhou,Guangdong,China [2]Department of Critical Care Medicine,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,China

出　　处：《Research》2025年第1期149-163,共15页研究(英文)

基　　金：supported by the National Natural Science Foundation of China(32300730);the Guangdong Science and Technology Department(2023B12120600280);the National Postdoctoral Program for Innovative Talents of China(BX20220365);the China Postdoctoral Science Foundation(2023M734057);the Fundamental Research Funds for the Central Universities(23yxqntd001).

摘　　要：As a key executioner of pyroptosis,Gasdermin D(GSDMD)plays a crucial role in host defense and emerges as an essential therapeutic target in the treatment of inflammatory diseases.So far,the understanding of the mechanisms that regulate the protein level of GSDMD to prevent detrimental effects and maintain homeostasis is currently limited.Here,we unveil that ubiquitin-specific peptidase 18(USP18)works as a negative regulator of pyroptosis by targeting GSDMD for degradation and preventing excessive innate immune responses.Mechanically,USP18 recruits E3 ubiquitin ligase mind bomb homolog 2(MIB2)to catalyze ubiquitination on GSDMD at lysine(K)168,which acts as a recognition signal for the selective autophagic degradation of GSDMD.We further confirm the alleviating effect of USP18 on LPS-triggered inflammation in vivo.Collectively,our study demonstrates the role of USP18 in regulating GSDMD-mediated pyroptosis and reveals a previously unknown mechanism by which GSDMD protein level is rigorously controlled by selective autophagy.

关 键 词：USP excessive innate immun host defense innate immune responses ubiquitin specific peptidase selective autophagy 

分 类 号：R392[医药卫生—免疫学]