Controlling pyroptosis through post-translational modifications of gasdermin D

Dev Cell. 2025 Apr 7;60(7):994-1007. doi: 10.1016/j.devcel.2025.02.005.

Abstract

Pyroptosis, a lytic and programmed cell death pathway, is mediated by gasdermins (GSDMs), with GSDMD playing an important role in innate immunity and pathology. Upon activation, GSDMD is cleaved to release the active N-terminal fragment that oligomerizes into membrane pores, which promote pyroptosis and cytokine secretion, leading to inflammation. Emerging evidence indicates that post-translational modification (PTM) is an important regulatory mechanism of GSDMD activity. This review explores how PTMs, aside from proteolytic cleavage, control GSDMD activity and link biological contexts to pyroptosis in innate immunity and inflammation, which could inform future studies and therapeutic solutions for treating inflammatory conditions.

Keywords: GSDMD; gasdermin; palmitoylation; phosphorylation; pore forming; post-translational modification; pyroptosis; ubiquitination.

Publication types

  • Review
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gasdermins
  • Humans
  • Immunity, Innate
  • Inflammation / metabolism
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Neoplasm Proteins* / metabolism
  • Phosphate-Binding Proteins* / metabolism
  • Protein Processing, Post-Translational*
  • Pyroptosis* / physiology

Substances

  • Phosphate-Binding Proteins
  • GSDMD protein, human
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Gasdermins