USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D
Liqiu Wang,
Mengqiu Li,
Guangyu Lian,
Shuai Yang,
Yaoxing Wu,
Jun Cui
Affiliations
Liqiu Wang
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.
Mengqiu Li
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.
Guangyu Lian
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.
Shuai Yang
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.
Yaoxing Wu
Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Jun Cui
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.
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.
