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ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D
Gang Du1,2, Liam B Healy3,4, Liron David5,6,7
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. gdu@crystal.harvard.edu.
Nature
|April 10, 2024
Summary
Gasdermin D (GSDMD) is palmitoylated, a modification essential for pore formation during pyroptosis. This reversible palmitoylation acts as a crucial switch for GSDMD activation, challenging previous notions of cleavage being the sole trigger.
Area of Science:
- Cellular Biology
- Immunology
- Biochemistry
Background:
- Gasdermin D (GSDMD) is a key effector in inflammasome activation, mediating cytokine secretion and pyroptosis by forming transmembrane pores.
- GSDMD pore formation has been primarily attributed to its N-terminal domain (GSDMD-NT) generated by caspase cleavage.
Purpose of the Study:
- To investigate the role of post-translational modifications beyond cleavage in GSDMD activation.
- To identify novel regulatory mechanisms controlling GSDMD-mediated pyroptosis.
Main Methods:
- Assessing GSDMD palmitoylation at Cys191 using biochemical assays.
- Investigating the impact of S-palmitoylation on GSDMD pore formation and pyroptosis using cleavage-deficient mutants and liposome leakage assays.
- Identifying GSDMD palmitoyltransferases (ZDHHC5, ZDHHC9) and analyzing their regulation by inflammasome activation and reactive oxygen species (ROS).
Main Results:
- GSDMD Cys191 is S-palmitoylated, and this modification is critical for pore formation, independent of caspase cleavage.
- Mitochondria-derived reactive oxygen species (ROS) enhance GSDMD palmitoylation.
- Palmitoylated GSDMD, including cleavage-deficient forms, induces liposome leakage and pyroptosis, with palmitoylation acting as a key activation switch for the gasdermin family.
Conclusions:
- Reversible S-palmitoylation is a critical checkpoint for Gasdermin D pore formation and pyroptosis, acting as a general activation switch for the gasdermin family.
- This finding challenges the paradigm that caspase-mediated cleavage is the sole trigger for GSDMD activation.
- Palmitoylation represents a novel therapeutic target for modulating inflammatory responses.
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