Gasdermin (GSDM) Family

The gasdermin (GSDM) family comprises the pore-forming executioner proteins of pyroptosis: GSDMA, GSDMB, GSDMC, GSDMD, GSDME, and the hearing-related DFNB59/PJVK. Each (except DFNB59) shares a two-domain architecture — an N-terminal pore-forming domain held inactive by a C-terminal inhibitory domain. Proteolytic cleavage of the linker between these domains, carried out by different proteases depending on the gasdermin (inflammatory caspases for GSDMD, executioner caspases for GSDME, granzymes for GSDMB/GSDME), releases the N-terminal domain to oligomerize into large pores in the plasma membrane. In cancer, gasdermin genes are frequently silenced (e.g., GSDME promoter hypermethylation) or spliced into pore-incompetent isoforms (certain GSDMB variants) as a mechanism to evade pyroptotic killing by cytotoxic lymphocytes.