GSDMD Protein, Human (His)

Cleaved N-terminal GSDMD is a precursor of a pore-forming protein that plays a key role in host defense against pathogen infection and danger signals. Upon cleavage, the released N-terminal moiety (Gasdermin-D, N-terminal) binds to membranes and forms pores, triggering pyroptosis. It is produced by the cleavage of gasdermin-D by inflammatory caspases (CASP1, CASP4, or CASP5) in response to canonical or non-canonical (e.g., cytosolic LPS) inflammasome activators. After cleavage, it moves to the plasma membrane, strongly binds to inner leaflet lipids (e.g., monophosphorylated phosphatidylinositols, bisphosphorylated phosphatidylinositols), and forms pores of 10-15 nm in diameter, releasing mature interleukin-1 (IL1B and IL18) and inducing pyroptosis. Gasdermin pores also allow the release of mature caspase-7 (CASP7) (by similar). In some cell types, pyroptosis is followed by pyroptotic cell death mediated by downstream ninjurin-1 (NINJ1), causing membrane rupture (cytolysis). It can also form pores in the mitochondrial membrane, releasing mitochondrial DNA (mtDNA) into the cytosol (by similar). The extracellularly released Gasdermin-D, N-terminal binds to and kills Gram-negative and Gram-positive bacteria without harming mammalian cells due to lipid-binding specificity. It is also active against intracellular bacteria (e.g., Listeria monocytogenes) under cell culture conditions (by similar). It is activated in response to Yersinia toxin YopJ-mediated inactivation of MAP3K7/TAK1, leading to cleavage by CASP8 (by similar), and is involved in mucosal defense against enteric pathogens (by similar). Excessive activation of the non-canonical inflammasome in brain endothelial cells can lead to pyroptosis and blood-brain barrier breakdown (by similar). Additionally, it is cleaved by CASP3 or CASP7 in the upper small intestine, acting as a transcription coactivator to maintain food tolerance (by similar). It is also cleaved by the papain allergen, forming pores and specifically releasing mature interleukin-33 (IL33) to promote type 2 inflammatory immune responses.