A critical role for palmitoylation in pyroptosis

Area of Science:

• Cellular biology
• Molecular mechanisms of cell death
• Protein modification

Background:

• Gasdermin D (GSDMD) is a key executioner protein in pyroptosis, a highly inflammatory form of programmed cell death.
• GSDMD activation leads to plasma membrane permeabilization, releasing pro-inflammatory cytokines.
• The precise molecular events regulating GSDMD translocation and oligomerization remain under investigation.

Purpose of the Study:

• To elucidate the role of post-translational modifications in regulating Gasdermin D function.
• To identify specific sites and mechanisms controlling GSDMD membrane association and pore formation.
• To understand how these modifications impact pyroptosis execution.

Main Methods:

• Analysis of protein-palmitoylation.
• Site-directed mutagenesis of Gasdermin D.
• Biochemical assays to assess protein translocation and oligomerization.
• Cellular assays to measure plasma membrane permeabilization and pyroptosis.

Main Results:

• Palmitoylation on cysteine residues 191 and 192 of Gasdermin D was identified as a critical regulatory event.
• This specific palmitoylation modification directly influences GSDMD's ability to translocate to the plasma membrane.
• Palmitoylation at Cys191/192 is essential for GSDMD oligomerization and subsequent plasma membrane permeabilization during pyroptosis.

Conclusions:

• Palmitoylation of Gasdermin D at Cys191/192 is a key determinant of its function in pyroptosis.
• This modification is crucial for GSDMD membrane translocation, oligomerization, and plasma membrane permeabilization.
• Understanding this regulatory mechanism provides insights into controlling inflammatory cell death pathways.