Gasdermin

Gasdermins are a family of pore-forming proteins that mediate a form of inflammatory programmed cell death called pyroptosis. They share a conserved architecture consisting of an N-terminal pore-forming domain and a C-terminal regulatory domain that keeps the protein inactive until proteolytic activation. Upon cleavage by specific proteases, the N-terminal fragment is released, oligomerizes, and inserts into the plasma membrane to form pores. This disrupts cellular integrity, leading to cell lysis and the release of inflammatory mediators.

In humans, the gasdermin family includes six paralogs: GSDMA, GSDMB, GSDMC, GSDMD, GSDME (also known as DFNA5), and GSDMF (also known as DFNB59). The best-characterized member is GSDMD, which is cleaved by inflammatory caspases—caspase-1, caspase-4, and caspase-5 in humans (caspase-11 in mice)—to generate the GSDMD-N fragment that forms membrane pores. Other family members can be activated by different proteases; for example, caspase-3 cleaves GSDME, linking apoptosis to pyroptosis in some contexts, and granzymes can activate certain gasdermins in cytotoxic responses. Caspase-8–mediated cleavage has also been described for GSDMC in specific signaling settings.

Physiologically, gasdermins participate in host defense by promoting the clearance of infected cells and driving inflammatory signaling. Dysregulation of gasdermin activity is associated with inflammatory diseases, sepsis, and cancer, making these proteins a focus of research aimed at modulating inflammatory responses and pyroptosis for therapeutic purposes.