GSDMD

Gasdermin D is a member of the gasdermin family. Members of this family appear to play a role in regulation of epithelial proliferation. Gasdermin D has been suggested to act as a tumor suppressor. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2009]

Gasdermin D

Gasdermin-D:
Precursor of a pore-forming protein that plays a key role in host defense against pathogen infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:27281216).

This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-D, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:26375003, PubMed:26375259, PubMed:27281216).

Gasdermin-D, N-terminal:
Promotes pyroptosis in response to microbial infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:27418190, PubMed:28392147, PubMed:32820063).

Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1, CASP4 or CASP5 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators (PubMed:26375003, PubMed:26375259, PubMed:27418190).

After cleavage, moves to the plasma membrane where it strongly binds to inner leaflet lipids, including monophosphorylated phosphatidylinositols, such as phosphatidylinositol 4-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, as well as phosphatidylinositol (3,4,5)-bisphosphate, and more weakly to phosphatidic acid and phosphatidylserine (PubMed:27281216, PubMed:29898893).

Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature IL1B and triggering pyroptosis (PubMed:27418190, PubMed:27281216, PubMed:29898893).

Exhibits bactericidal activity (PubMed:27281216).

Gasdermin-D, N-terminal released from pyroptotic cells into the extracellular milieu rapidly binds to and kills both Gram-negative and Gram-positive bacteria, without harming neighboring mammalian cells, as it does not disrupt the plasma membrane from the outside due to lipid-binding specificity (PubMed:27281216).

Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes (By similarity).

Also active in response to MAP3K7/TAK1 inactivation by Yersinia toxin YopJ, which triggers cleavage by CASP8 and subsequent activation (By similarity).

Strongly binds to bacterial and mitochondrial lipids, including cardiolipin (PubMed:27281216).

Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine (PubMed:27281216).

Defense response to bacterium Source: GO_Central
Defense response to Gram-negative bacterium Source: UniProtKB
Defense response to Gram-positive bacterium Source: UniProtKB
Inflammatory response Source: UniProtKB-KW
Innate immune response Source: UniProtKB-KW
Neutrophil degranulation Source: Reactome
Pore complex assembly Source: UniProtKB
Pore formation in membrane of other organism Source: UniProtKB
Positive regulation of interleukin-1 beta production Source: UniProtKB
Protein homooligomerization Source: UniProtKB
Pyroptosis Source: UniProtKB

Gasdermin-D: Cytosol; Inflammasome. In response to a canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 inflammasone with similar kinetics to that of uncleaved CASP1 precursor.
Gasdermin-D, N-terminal: Secreted; Cell membrane. Released in the extracellular milieu following pyroptosis.
Gasdermin-D, C-terminal: Cytosol

Cleavage at Asp-275 by CASP1 (mature and uncleaved precursor forms), CASP4, CASP5 or CASP8 relieves autoinhibition and is sufficient to initiate pyroptosis (PubMed:26375003, PubMed:29898893, PubMed:32109412). Cleavage by CASP1 and CASP4 is not strictly dependent on the consensus cleavage site on GSDMD but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412). Cleavage by CASP8 takes place following inactivation of MAP3K7/TAK1 by Yersinia toxin YopJ (By similarity). Cleavage at Asp-87 by CASP3 or CAPS7 inactivates the ability to mediate pyroptosis (PubMed:28392147, PubMed:28045099).
Gasdermin-D:
Succination of Cys-191 by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits processing by caspases, and ability to initiate pyroptosis (PubMed:32820063). Succination modification is catalyzed by a non-enzymatic reaction caused by an accumulation of fumarate (PubMed:32820063).