GSDMD gene

The GSDMD gene (GSDMD stands for: Gasdermin Domain Containing) is a protein-coding gene located on chromosome 8q24.3.

The GSDMD gene encodes gasdermin, the precursor of a pore-forming protein that plays a key role in the host's defense against pathogens and danger signals. (Shi J et al. 2015). Upon its cleavage, the released N-terminal portion (gasdermin-D, N-terminal) binds to membranes and forms pores, triggering pyroptosis (Tayagaki N et al. 2015).

Gasdermin promotes pyroptosis in response to microbial infections and danger signals (PubMed:26375003, 26375259, 27418190, 28392147, 32820063). Produced by the cleavage of gasdermin-D by the inflammatory caspases CASP1, CASP4 or CASP5 in response to canonical and non-canonical (e.g. cytosolic LPS) inflammasome activators (PubMed:26375003, 26375259, 27418190). After cleavage, it migrates to the plasma membrane, where it binds strongly to the lipids of the inner leaflets, including monophosphorylated phosphatidylinositols such as phosphatidylinositol-4-phosphate, bisphosphorylated phosphatidylinositols such as phosphatidylinositol-(4,5)-bisphosphate and phosphatidylinositol-(3,4). ,5)-bisphosphate and more weakly to phosphatidic acid and phosphatidylserine (Kayagaki N et al. 2015). Homooligomerizes within the membrane and forms pores with an inner diameter of 10-15 nanometers (nm), which enables the release of mature interleukin-1 (IL1B and IL18) and triggers pyroptosis. Gasdermin pores also facilitate the release of mature caspase-7 (CASP7). Gasdermin also forms pores in the mitochondrial membrane, which leads to the release of mitochondrial DNA (mtDNA) into the cytosol.

Furthermore, gasdermin-D, which is released from pyroptotic cells into the extracellular milieu, binds very quickly to Gram-negative and Gram-positive bacteria and kills them without damaging neighboring mammalian cells, as it does not destroy the plasma membrane from the outside with lipids. Under cell culture conditions, the protein is also effective against intracellular bacteria such as Listeria monocytogenes. Gasdermin binds strongly to bacterial and mitochondrial lipids, including cardiolipin.

Diseases associated with GSDMD include Cinca syndrome (familial autoinflammatory cold syndrome). Associated signaling pathways include the innate immune system and inflammasomes.

1. Kayagaki N et al. (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signaling. Nature 526:666-671.
2. Shi J et al. (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660-665.
3. Sborgi L et al. (2016) GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 35:1766-1778.