page_title: GSDMD
section_title: Mechanism
hierarchical_section_title: GSDMD / Mechanism
caption_attribution_description: English: Overview of GSDMD
context_page_description: Gasdermin D is a protein that in humans is encoded by the GSDMD gene on chromosome 8.
  It belongs to the gasdermin family which is conserved among all vertebrates and comprises six members, GSDMA, GSDMB, GSDMC, GSDMD, GSDME and DFNB59. Members of the gasdermin family are mainly expressed in epithelial tissues and appear to play a role in regulation of epithelial proliferation and differentiation. GSDMA, GSDMC, GSDMD and DFNA5 have been suggested to act as tumour suppressors.
context_section_description: After the proteolytic cleavage, GSDMD-C remains in the cytosol while the N-terminal cleavage product localises to the plasma membrane by anchoring to  membrane lipids. GSDMD-N specifically interacts with phosphatidylinositol 4-phosphate [PI(4)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] on the inner leaflet of mammalian cell membrane strongly, through charge-charge interactions between the negatively-charged head groups of PI and the positively-charged surface on GSDMD-N exposed after cleavage. Hence, collateral damage to tissues during an infection is minimised as the extracellular outer leaflet lacks PI. Lipid binding allows GSDMD-N to insert into the lipid bilayer and induces high-order oligomerisation within the membrane, forming extensive pores with approximately 16 subunits and an inner diameter of 10-14 nm. The osmotic potential is disrupted by pore formation, leading to cell swelling and lysis, the morphologic hallmarks of pyroptosis. The pores also serve as a protein secretion channel to facilitate the secretion of inflammatory cytokines for rapid innate immune response. GSDMD-N can also undergo cytoplasmic distribution and selectively bind to CL on inner and outer leaflets of intracellular bacterial membranes, or be secreted from pyroptotic cells through the pores into the extracellular milieu to target and kill extracellular bacteria.
caption: Overview of GSDMD activation and pore-forming mechanism
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