GSDME

GSDME, or gasdermin E, is a human gene encoding the Gasdermin E protein, a member of the gasdermin family. The full-length protein contains an N-terminal pore-forming domain and a C-terminal autoinhibitory domain; in its intact form, the protein remains inactive due to intramolecular inhibition between the two regions.

A key feature of GSDME is its activation by caspase-3. When caspase-3 cleaves GSDME at a conserved aspartic acid residue (around Asp270), the N-terminal fragment is released. This N-terminal fragment can translocate to the plasma membrane, oligomerize, and form pores, driving pyroptotic cell death and the release of inflammatory signals. This mechanism links apoptosis to inflammatory forms of cell death.

Clinical and research relevance is multifaceted. Pathogenic variants in GSDME/DFNA5 are associated with autosomal dominant nonsyndromic hearing loss, typically due to splice-site mutations that disrupt the C-terminal domain and produce toxic fragments in cochlear cells. In cancer biology, GSDME expression is frequently silenced by promoter methylation in tumors; when GSDME is expressed and cells undergo apoptosis with caspase-3 activation, the resulting pyroptosis can enhance anti-tumor immunity and influence chemotherapy responses. Thus, GSDME activity may affect treatment outcomes and is being explored as a potential biomarker and therapeutic consideration.

GSDME is one member of the gasdermin family, which comprises related proteins involved in inflammatory forms of cell death.