USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D

Liqiu Wang; Mengqiu Li; Guangyu Lian; Shuai Yang; Yaoxing Wu; Jun Cui

doi:10.34133/research.0380

USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D

Research (Wash D C). 2024 May 22:7:0380. doi: 10.34133/research.0380. eCollection 2024.

Authors

Liqiu Wang¹, Mengqiu Li¹, Guangyu Lian¹, Shuai Yang¹, Yaoxing Wu², Jun Cui¹

Affiliations

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.

Abstract

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.