Expression starts at 8.5 dpc and increases from 13.5 dpc on. Still detected after birth.
Intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of cleavage by inflammatory caspases CASP1 or CASP4/CASP11 (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:29576317, PubMed:31097341). The linker helix loop inserts into the N-terminal domain (By similarity). The intrinsic pyroptosis-inducing activity is carried by Gasdermin-D, N-terminal, that is released upon cleavage by inflammatory caspases (PubMed:26375003, PubMed:26375259, PubMed:26611636).
Gasdermin-D, N-terminal
Forms a ring-shaped pore complex containing 27-28 subunits that inserts into the membrane. The pore conduit is predominantly negatively charged, facilitating the release of mature interleukin-1 (IL1B and IL18). In contrast interleukin-1 precursors are not released, due to the presence of an acidic region that is proteolytically removed by CASP1 during maturation.
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:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190). 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:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190).
Gasdermin-D, N-terminal
Promotes pyroptosis in response to microbial infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190, PubMed:32820063, PubMed:34289345, PubMed:35705808, PubMed:37988464, PubMed:38530158, PubMed:38538834, PubMed:38632402). Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1 or CASP4/CASP11 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190, PubMed:35705808, PubMed:38632402). 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:27339137, PubMed:27383986). Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukin-1 (IL1B and IL18) and triggering pyroptosis (PubMed:27383986, PubMed:29195811, PubMed:29274245, PubMed:33883744, PubMed:38530158, PubMed:38538834). Gasdermin pores also allow the release of mature caspase-7 (CASP7) (PubMed:35705808). In some, but not all, cells types, pyroptosis is followed by pyroptotic cell death, which is caused by downstream activation of ninjurin-1 (NINJ1), which mediates membrane rupture (cytolysis) (PubMed:38632402). Also forms pores in the mitochondrial membrane, resulting in release of mitochondrial DNA (mtDNA) into the cytosol (PubMed:37001519). 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:27383986). Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes (PubMed:27383986). Also active in response to MAP3K7/TAK1 inactivation by Yersinia toxin YopJ, which triggers cleavage by CASP8 and subsequent activation (PubMed:30361383, PubMed:30381458). Required for mucosal tissue defense against enteric pathogens (PubMed:37988464). Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown (PubMed:38632402). Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine (PubMed:27383986).
Gasdermin-D, p13
Transcription coactivator produced by the cleavage by CASP3 or CASP7 in the upper small intestine in response to dietary antigens (PubMed:37327784). Required to maintain food tolerance in small intestine: translocates to the nucleus and acts as a coactivator for STAT1 to induce the transcription of CIITA and MHC class II molecules, which in turn induce type 1 regulatory T (Tr1) cells in upper small intestine (PubMed:37327784).
Gasdermin-D, p40
Produced by the cleavage by papain allergen (PubMed:35794369). After cleavage, moves to the plasma membrane and homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the specific release of mature interleukin-33 (IL33), promoting type 2 inflammatory immune response (PubMed:35749514, PubMed:35794369).
Cleavage at Asp-276 by CASP1 (mature and uncleaved precursor forms), CASP4/CASP11 or CASP8 relieves autoinhibition and is sufficient to initiate pyroptosis (PubMed:26375259, PubMed:26611636, PubMed:32553275, PubMed:32554464). Cleavage by CASP1 and CASP4/CASP11 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:32553275, PubMed:32554464). Cleavage by CASP8 takes place following inactivation of MAP3K7/TAK1 by Yersinia toxin YopJ (PubMed:30361383, PubMed:30381458). Cleavage at Asp-88 by CASP3 or CASP7 inactivates the ability to mediate pyroptosis, but generates the Gasdermin-D, p13 chain, which translocates to the nucleus and acts as a transcription regulator (PubMed:37327784). Cleavage by papain allergen generates the Gasdermin-D, p40 chain (PubMed:35794369).
Gasdermin-D
Palmitoylated at Cys-192 by ZDHHC5 and ZDHHC9 in response to microbial infection and danger signals (PubMed:38324683, PubMed:38530158, PubMed:38599239). May also be palmitoylated by ZDHHC7 (PubMed:38538834). Palmitoylation takes place before cleavage by caspases (CASP1, CASP4, CASP5 or CASP8) and is required for membrane translocation and pore formation (PubMed:38324683, PubMed:38530158, PubMed:38538834, PubMed:38599239). Depalmitoylated by LYPLA2 (PubMed:38538834).
Gasdermin-D
Succination of Cys-192 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).
Glycosylated: O-GlcNAcylation by OGT leads to reduced cleavage by CASP4 and decreased LPS-induced endothelial cell pyroptosis.
Belongs to the gasdermin family.
Highly expressed in brain endothelial cells.
Gsdmdc1, Gsdmd, Gasdermin-D, Gasdermin domain-containing protein 1
Proteins
Immunology & Infectious Disease
53238Da
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