Gsdmd Conditional Knockout mouse models

Gsdmd is the mouse ortholog of human GSDMD and encodes gasdermin D, a two-domain protein in which an autoinhibitory C-terminal domain restrains an N-terminal pore-forming module. Inflammatory caspase-1 and caspase-11, and in some settings caspase-8 or neutrophil elastase, cleave the interdomain linker at Asp276 in mouse, liberating the p30 fragment that binds acidic membrane lipids, oligomerizes into large beta-barrel pores, and provides the conduit for mature interleukin 1 beta and interleukin 18 export before NINJ1 dependent membrane rupture completes pyroptosis. Allele choice maps onto mechanism directly: a conditional null removes both cytokine release and lytic death, a D276A noncleavable knockin isolates processing from expression, and pore-dead point mutants separate lysis from unconventional secretion. Gsdme and the Gsdma cluster execute overlapping lytic programs downstream of caspase-3 or bacterial proteases, so pyroptosis-resistant phenotypes may require compound alleles, and myeloid restricted Cre lines assign the death to the intended lineage.

Tissue restricted knockout of Gsdmd keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.