Gasdermin D

Gasdermin D is a protein that in humans is encoded by the GSDMD gene on chromosome 8. It belongs to the gasdermin family, which is conserved in vertebrates and comprises six members in humans:

GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and DFNB59.

Members of the gasdermin family are expressed in a variety of cell types, including epithelial cells and immune cells. It has been suggested that GSDMA, GSDMB, GSDMC, GSDMD and GSDME act as tumor suppressors.

Several recent studies have shown that GSDMD serves as a specific substrate of inflammatory caspases(caspase-1, -4, -5 and -11) and as an effector molecule for the lytic and highly inflammatory form of programmed cell death known as pyroptosis(Huston HC et al. 2023). GSDMD can be cleaved and activated by inflammatory caspases via both the canonical and non-canonical pyroptotic pathways.

Canonical inflammasome pathway: Caspase-1, which is conserved in vertebrates, is involved in the canonical signaling pathway and is activated by canonical inflammasomes such as NLRP3 and NLRC4 inflammasomes. These are multiprotein complexes that are activated by NOD-like receptors (NLRs) in the cytosol upon recognition of specific inflammatory ligands ("pathogen-associated molecular patterns/PAMPs" and "Danger-associated molecular patterns/DAMPs). Examples are the rod protein and flagellin of the bacterial type 3 secretion system (T3SS), which are strong activators of the NLRC4 inflammasome, and the bacterial toxin nigericin, which activates the NLRP3 inflammasome.

Non-canonical inflammasome signaling pathway: Caspases 4 and 5 are involved in the non-canonical signaling pathway and are activated by direct binding of cytosolic lipopolysaccharide (LPS) secreted by Gram-negative bacteria. Upon activation of these caspases, GSDMD undergoes proteolytic cleavage sufficient to drive pyroptosis. Therefore, GSDMD is an essential mediator of host defense against microbial infections and danger signals. The pore-forming activity of the N-terminal cleavage product leads to swelling and lysis of cells to prevent replication of intracellular pathogens and is required for the release of cytoplasmic contents such as the inflammatory cytokine interleukin-1β (IL-1β) into the extracellular space to recruit and activate immune cells at the site of infection. GSDMD plays an additional potential role as an antimicrobial agent by binding to cardiolipin (CL) and forming pores on bacterial membranes.

Under normal conditions, full-length GSDMD is inactive because the linker loop between the N-terminal and C-terminal domains stabilizes the overall conformation of the full-length protein, allowing GSDMD-C to refold and automatically inhibit GSDMD-C. Pyroptosis is prevented. Upon interdomain cleavage by inflammatory caspases, auto-inhibition is abolished and GSDMD cytotoxicity is triggered.

1. Shi J et al. (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660-665.

2. Huston HC et al. (2023) Pyroptosis and the cellular consequences of gasdermin pores. Semin Immunol 69:101803.

3. Kayagaki N et al. (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signaling. Nature 526:666-671.

4. Sborgi L et al. (2016) GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 35:1766-1778.