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Details on Person UniProt:P57764 GSDMD
| Class:Id | ReferenceGeneProduct:53562 |
|---|---|
| _chainChangeLog | chain:1-484 added on Sat February 7 2015;chain:1-275 added on Fri November 4 2016;chain:276-484 added on Fri November 4 2016;chain:1-290 for 53562 added on Mon Feb 26 2024;chain:1-87 for 53562 added on Mon Feb 26 2024 |
| _displayName | UniProt:P57764 GSDMD |
| _timestamp | 2024-11-03 20:05:35 |
| chain | chain:1-484 chain:1-290 chain:1-275 chain:1-87 chain:276-484 |
| checksum | F7CE8073E0C0194D |
| comment | FUNCTION 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).FUNCTION Promotes pyroptosis in response to microbial infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:27418190, PubMed:28392147, PubMed:32820063, PubMed:34289345, PubMed:38040708, PubMed:38530158, PubMed:38599239). 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, PubMed:36227980). 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:27281216, PubMed:27418190, PubMed:29898893, PubMed:33883744, PubMed:38040708, PubMed:38530158, PubMed:38599239). Gasdermin pores also allow the release of mature caspase-7 (CASP7) (By similarity). 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:33472215, PubMed:37198476). Also forms pores in the mitochondrial membrane, resulting in release of mitochondrial DNA (mtDNA) into the cytosol (By similarity). 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). Required for mucosal tissue defense against enteric pathogens (By similarity). Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown (By similarity). Strongly binds to bacterial and mitochondrial lipids, including cardiolipin (PubMed:27281216). Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine (PubMed:27281216).FUNCTION Transcription coactivator produced by the cleavage by CASP3 or CASP7 in the upper small intestine in response to dietary antigens (By similarity). 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 (By similarity).FUNCTION 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:35794369).ACTIVITY REGULATION The full-length protein before cleavage is inactive: intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of activation signal (PubMed:26375003, PubMed:28928145, PubMed:29576317, PubMed:32109412). The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-D, N-terminal) following cleavage by caspases CASP1, CASP4, CASP5 or CASP8 (PubMed:26375003, PubMed:26375259, PubMed:27418190, PubMed:29898893, PubMed:32109412). Cleavage at Asp-87 by CASP3 or CASP7 inactivates the ability to mediate pyroptosis (PubMed:28392147). Homooligomerization and pore formation is specifically inhibited by VHH(GSDMD-1) and, to a lesser extent, VHH(GSDMD-2) nanobodies, protecting against excessive pyroptosis (PubMed:38040708). Inhibited by small molecule NU6300, which covalently reacts with Cys-191, thereby preventing palmitoylation and pyroptosis (PubMed:38324683).SUBUNIT Homooligomer; homooligomeric ring-shaped pore complex containing 27-28 subunits when inserted in the membrane (PubMed:33883744, PubMed:34289345, PubMed:38040708). Homooligomerization is promoted by the mTORC1 complex in macrophages (PubMed:34289345). In response to a canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 inflammasone with similar kinetics to that of uncleaved CASP1 precursor (By similarity). Although this recruitment is also observed in the absence of PYCARD, it is more efficient in its presence (By similarity).INTERACTION In response to a canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 inflammasone with similar kinetics to that of uncleaved CASP1 precursor.SUBCELLULAR LOCATION Released in the extracellular milieu following pyroptosis.SUBCELLULAR LOCATION (Microbial infection) Upon infection by M.tuberculosis, localization to cell membrane is prevented by M.tuberculosis phosphatase PtpB that catalyzes dephosphorylation of phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol 4-phosphate, thereby inhibiting the membrane targeting of Gasdermin-D, N-terminal and subsequent cytokine release and pyroptosis.SUBCELLULAR LOCATION Expressed in the suprabasal cells of esophagus, as well as in the isthmus/neck, pit, and gland of the stomach, suggesting preferential expression in differentiating cells.DOMAIN Intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of cleavage by inflammatory caspases CASP1, CASP4 or CASP5 (PubMed:26375003, PubMed:28928145, PubMed:29576317, PubMed:29898893). The linker helix loop inserts into the N-terminal domain (PubMed:28928145). The intrinsic pyroptosis-inducing activity is carried by Gasdermin-D, N-terminal, that is released upon cleavage by inflammatory caspases (PubMed:26375003).DOMAIN Forms a ring-shaped pore complex containing 27-28 subunits that inserts into the membrane (PubMed:33883744). The pore conduit is predominantly negatively charged, facilitating the release of mature interleukin-1 (IL1B and IL18) (PubMed:33883744). In contrast interleukin-1 precursors are not released, due to the presence of an acidic region that is proteolytically removed by CASP1 during maturation (PubMed:33883744).PTM 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 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:28045099, PubMed:28392147, PubMed:37327784). Cleavage by papain allergen generates the Gasdermin-D, p40 chain (PubMed:35794369).PTM Palmitoylated at Cys-191 by ZDHHC5 and ZDHHC9 in response to microbial infection and danger signals (PubMed:38324683, PubMed:38530158, PubMed:38599239). 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:38599239). Depalmitoylated by LYPLA2 (By similarity).PTM 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).PTM Glycosylated: O-GlcNAcylation by OGT leads to reduced cleavage by CASP4 and decreased LPS-induced endothelial cell pyroptosis.PTM (Microbial infection) Cleaved and inactivated by Protease 3C from Human enterovirus 71 (EV71), preventing GSDMD-mediated pyroptosis.PTM (Microbial infection) Cleaved and inactivated by the 3C-like proteinase nsp5 from human coronavirus SARS-CoV-2, preventing GSDMD-mediated pyroptosis.PTM (Microbial infection) Ubiquitinated by S.flexneri IpaH7.8, leading to its degradation by the proteasome.SIMILARITY Belongs to the gasdermin family. |
| description | recommendedName: fullName evidence="36"Gasdermin-D alternativeName: fullName evidence="34"Gasdermin domain-containing protein 1 component recommendedName: fullName evidence="41"Gasdermin-D, N-terminal shortName evidence="2"GSDMD-NT shortName evidence="37"hGSDMD-NTD /component component recommendedName: fullName evidence="41"Gasdermin-D, C-terminal shortName evidence="2"GSDMD-CT shortName evidence="37"hGSDMD-CTD /component component recommendedName: fullName evidence="41"Gasdermin-D, p13 alternativeName: fullName evidence="39"Gasdermin-D, 13 kDa shortName evidence="39"13 kDa GSDMD /component component recommendedName: fullName evidence="38"Gasdermin-D, p40 /component |
| geneName | GSDMD DFNA5L GSDMDC1 FKSG10 |
| identifier | P57764 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Cell membrane Cytoplasm Direct protein sequencing Glycoprotein Immunity Inflammasome Inflammatory response Innate immunity Lipid-binding Lipoprotein Membrane Mitochondrion Necrosis Nucleus Palmitate Phosphoprotein Proteomics identification Reference proteome Secreted Transcription Transcription regulation Transmembrane Transmembrane beta strand Ubl conjugation |
| modified | [InstanceEdit:84067] Schmidt, EE, 2003-12-18 04:29:09 [InstanceEdit:143527] Schmidt, EE, 2004-11-12 07:45:10 [InstanceEdit:217385] Schmidt, EE, 2008-03-27 06:23:53 [InstanceEdit:354386] Schmidt, EE, 2008-06-18 04:45:12 [InstanceEdit:384350] Kanapin, AA, 2008-11-26 14:00:39 [InstanceEdit:392885] Kanapin, AA, 2009-03-09 12:07:18 [InstanceEdit:400710] Schmidt, EE, 2009-03-25 05:33:35 [InstanceEdit:423310] Kanapin, AA [InstanceEdit:435478] Kanapin, AA [InstanceEdit:435871] Kanapin, AA [InstanceEdit:447347] Kanapin, AA [InstanceEdit:525883] Kanapin, AA [InstanceEdit:613449] Kanapin, AA [InstanceEdit:797602] Kanapin, AA [InstanceEdit:937368] Yung, CK [InstanceEdit:1042053] Yung, CK [InstanceEdit:1220657] Yung, CK [InstanceEdit:1300696] Yung, CK [InstanceEdit:1301627] Yung, CK [InstanceEdit:1551960] Weiser, JD [InstanceEdit:1995863] Weiser, JD [InstanceEdit:2132304] Weiser, JD [InstanceEdit:2265580] Weiser, JD [InstanceEdit:5433710] Weiser, JD [InstanceEdit:5618415] Weiser, JD [InstanceEdit:5634237] Weiser, JD [InstanceEdit:5673015] Weiser, JD [InstanceEdit:8869714] Weiser, JD [InstanceEdit:8944791] Weiser, JD [InstanceEdit:8987656] Weiser, JD [InstanceEdit:9037114] Weiser, JD [InstanceEdit:9616384] Weiser, JD [InstanceEdit:9637257] Weiser, JD [InstanceEdit:9666080] Weiser, JD [InstanceEdit:9676415] Weiser, JD [InstanceEdit:9698430] Weiser, JD [InstanceEdit:9715482] Weiser, JD [InstanceEdit:9730071] Weiser, JD [InstanceEdit:9773244] Weiser, Joel [InstanceEdit:9829221] Weiser, Joel [InstanceEdit:9834092] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 |
| name | GSDMD |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8962108] ENSEMBL:ENSG00000104518 GSDMD [Homo sapiens] |
| secondaryIdentifier | GSDMD_HUMAN A8K702 D3DWJ9 Q96Q98 |
| sequenceLength | 484 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:6801468] GSDMD [specific granule lumen] [Homo sapiens] [EntityWithAccessionedSequence:6801498] GSDMD [ficolin-1-rich granule lumen] [Homo sapiens] [EntityWithAccessionedSequence:6801501] GSDMD [tertiary granule lumen] [Homo sapiens] [EntityWithAccessionedSequence:6801576] GSDMD [extracellular region] [Homo sapiens] [EntityWithAccessionedSequence:6801577] GSDMD [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9647641] GSDMD(1-275) [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9647672] GSDMD(276-484) [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9686099] GSDMD(1-87) [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9686133] GSDMD(88-484) [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9693317] dithiocarb-C191-GSDMD(1-275) [cytosol] [Homo sapiens] |
| (referenceSequence) | [GroupModifiedResidue:9693322] modified L-cysteine residue (diethyldithiocarbamate) at 191 [ModifiedResidue:9716196] S-(2-succinyl)-L-cysteine at 191 |
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No pathways have been reviewed or authored by UniProt:P57764 GSDMD (53562)
