A Palmitoylation-depalmitoylation Relay Spatiotemporally Controls GSDMD Activation in Pyroptosis

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2024 Mar 28

PMID 38538834

Authors

Na Zhang

Jian Zhang

Yuanxin Yang

Hengyue Shan

Shouqiao Hou

Hongwen Fang

Min Ma

Zhongwen Chen

Li Tan

Daichao Xu

Affiliations

Soon will be listed here.

Abstract

Gasdermin D (GSDMD) is the executor of pyroptosis, which is important for host defence against pathogen infection. Following activation, caspase-mediated cleavage of GSDMD releases an amino-terminal fragment (GSDMD-NT), which oligomerizes and forms pores in the plasma membrane, leading to cell death and release of proinflammatory cytokines. The spatial and temporal regulation of this process in cells remains unclear. Here we identify GSDMD as a substrate for reversible S-palmitoylation on C192 during pyroptosis. The palmitoyl acyltransferase DHHC7 palmitoylates GSDMD to direct its cleavage by caspases. Subsequently, palmitoylation of GSDMD-NT promotes its translocation to the plasma membrane, where APT2 depalmitoylates GSDMD-NT to unmask the C192 residue and promote GSDMD-NT oligomerization. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis, leading to increased survival of mice with lipopolysaccharide-induced lethal septic shock and increased sensitivity to bacterial infection. Our findings reveal a model through which a palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation during pyroptosis.

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