Dynamic S-acylation of GSDMA regulates pyroptosis

GSDMA, the primary member of the gasdermin family found in the skin, is critical for pathogen-induced pyroptosis during infection. Recent studies revealed that another gasdermin, GSDMD, undergoes palmitoylation during pyroptosis. However, whether and how the other gasdermin members undergo lipid modification remains poorly understood. Here, we demonstrate that GSDMA is S-acylated at the conserved cysteine residues in its N-terminal domain. We show that S-acylation of GSDMA promotes pyroptosis by facilitating its membrane anchoring and protein oligomerization, a mechanism distinct from the palmitoylation of GSDMD at the N-terminal C191 residue. Additionally, we present evidence that recombinant proteins of GSDMA and GSDMD can undergo S- acylation in vitro via direct interaction with palmitoyl-CoA, suggesting they potentially possess auto-acylation capacity. Furthermore, we identify ABHD17A as one of the deacylating enzymes that regulate the dynamic fatty acylation cycle of GSDMA. Overall, our studies reveal new molecular mechanisms underlying GSDMA function through S- acylation and underscore its important role in regulating pyroptosis mediated by GSDMA. HighlightsO_LIGSDMA is S-acylated at N-terminal conserved cysteine residues. C_LIO_LIGSDMA S-acylation facilitates membrane anchoring and protein oligomerization. C_LIO_LIGSDMA and GSDMD recombinant proteins can undergo S-acylation in vitro C_LIO_LIThe ABHD17A enzyme is involved in GSDMA deacylation. C_LI