Q9D8T2 · GSDMD_MOUSE
- ProteinGasdermin-D
- GeneGsdmd
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids487 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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).
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).
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).
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).
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).
Activity regulation
Gasdermin-D
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:26375259, PubMed:26611636, PubMed:29576317, PubMed:31097341).
The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-D, N-terminal) following cleavage by inflammatory caspases CASP1, CASP4/CASP11 or CASP8 (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:30361383, PubMed:30381458, PubMed:32553275, PubMed:32554464).
Cleavage at Asp-88 by CASP3 or CASP7 inactivates the ability to mediate pyroptosis (By similarity).
Pore formation is specifically inhibited by VHH(GSDMD-1) nanobody, protecting against excessive pyroptosis (PubMed:38632402).
Inhibited by small molecule NU6300, which covalently reacts with Cys-191, thereby preventing palmitoylation and pyroptosis (PubMed:38324683).
The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-D, N-terminal) following cleavage by inflammatory caspases CASP1, CASP4/CASP11 or CASP8 (PubMed:26375003, PubMed:26375259, PubMed:26611636, PubMed:30361383, PubMed:30381458, PubMed:32553275, PubMed:32554464).
Cleavage at Asp-88 by CASP3 or CASP7 inactivates the ability to mediate pyroptosis (By similarity).
Pore formation is specifically inhibited by VHH(GSDMD-1) nanobody, protecting against excessive pyroptosis (PubMed:38632402).
Inhibited by small molecule NU6300, which covalently reacts with Cys-191, thereby preventing palmitoylation and pyroptosis (PubMed:38324683).
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 88-89 | Cleavage; by CASP3 or CASP7 | ||||
Sequence: DG | ||||||
Site | 276-277 | Cleavage; by caspases CASP1, CASP4/CASP11 and CASP8 | ||||
Sequence: DG | ||||||
Site | 310-311 | Cleavage; by papain | ||||
Sequence: LR |
GO annotations
Keywords
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameGasdermin-D
- Alternative names
- Cleaved into 4 chains
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ9D8T2
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Gasdermin-D
Note: 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
Cell membrane ; Multi-pass membrane protein
Gasdermin-D, N-terminal
Note: (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.
Gasdermin-D, p13
Gasdermin-D, C-terminal
Features
Showing features for transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Transmembrane | 92-98 | Beta stranded | ||||
Sequence: QGRVMLS | ||||||
Transmembrane | 104-109 | Beta stranded | ||||
Sequence: KISGGA | ||||||
Transmembrane | 181-187 | Beta stranded | ||||
Sequence: GSGQFTL | ||||||
Transmembrane | 192-198 | Beta stranded | ||||
Sequence: CLKGEGK |
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Knockout mice are born at the expected Mendelian rate and do not exhibit any overt phenotype in normal housing conditions (PubMed:18693275, PubMed:26375003, PubMed:26375259).
The gastrointestinal tract develops normally (PubMed:18693275, PubMed:26375003, PubMed:26375259).
They are however resistant to LPS-induced lethal septic shock (PubMed:26375259).
Primary bone marrow-derived macrophages fail to undergo pyroptosis in response to canonical (acting via CASP1), as well as to non-canonical (acting via CASP4) inflammasome activators (PubMed:18693275, PubMed:26375003, PubMed:26375259).
CASP1-mediated IL1B release is also impaired, but not CASP1 autoprocessing, nor IL1B maturation (PubMed:18693275, PubMed:26375003, PubMed:26375259).
Reduced ability to protect against acute S.Typhimurium infection in the gut (PubMed:37988464).
Increased resistance of the blood-brain barrier following infection, due to decreased non-canonical inflammasome activation and pyroptosis of endothelial cells (PubMed:38632402).
The gastrointestinal tract develops normally (PubMed:18693275, PubMed:26375003, PubMed:26375259).
They are however resistant to LPS-induced lethal septic shock (PubMed:26375259).
Primary bone marrow-derived macrophages fail to undergo pyroptosis in response to canonical (acting via CASP1), as well as to non-canonical (acting via CASP4) inflammasome activators (PubMed:18693275, PubMed:26375003, PubMed:26375259).
CASP1-mediated IL1B release is also impaired, but not CASP1 autoprocessing, nor IL1B maturation (PubMed:18693275, PubMed:26375003, PubMed:26375259).
Reduced ability to protect against acute S.Typhimurium infection in the gut (PubMed:37988464).
Increased resistance of the blood-brain barrier following infection, due to decreased non-canonical inflammasome activation and pyroptosis of endothelial cells (PubMed:38632402).
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 7-14 | Reduced ability to induct pyroptosis. | ||||
Sequence: KVVKNVIK → AVVANVIA | ||||||
Mutagenesis | 17-20 | Renders Gsdmd susceptible to ubiquitination by S.flexneri IpaH7.8. | ||||
Sequence: SGSR → DGS | ||||||
Mutagenesis | 29 | Reduced homoolimerization, leading to reduced ability to induce pyroptosis. | ||||
Sequence: L → A | ||||||
Mutagenesis | 39 | Loss of oligomerization of Gasdermin-D, N-terminal. | ||||
Sequence: C → A | ||||||
Mutagenesis | 43-54 | Reduced ability to induce pyroptosis. | ||||
Sequence: RKFSSSRFWKPR → AAFSSSRFWAPA | ||||||
Mutagenesis | 50-51 | Abolished ability to form a pore, leading to educed ability to induce pyroptosis. | ||||
Sequence: FW → GG | ||||||
Mutagenesis | 57 | No effect on oligomerization. | ||||
Sequence: C → A | ||||||
Mutagenesis | 60 | Reduced homoolimerization, leading to reduced ability to induce pyroptosis. | ||||
Sequence: L → G | ||||||
Mutagenesis | 77 | No effect on oligomerization. | ||||
Sequence: C → A | ||||||
Mutagenesis | 81 | Reduced homoolimerization, leading to reduced ability to induce pyroptosis. | ||||
Sequence: F → D | ||||||
Mutagenesis | 85-88 | Abolished cleavage by CASP3 and CASP7. | ||||
Sequence: DVVD → AAAA | ||||||
Mutagenesis | 91 | Reduced homoolimerization, leading to reduced ability to induce pyroptosis. | ||||
Sequence: I → D | ||||||
Mutagenesis | 95 | Reduced homoolimerization, leading to reduced ability to induce pyroptosis. | ||||
Sequence: V → D | ||||||
Mutagenesis | 105 | Reduced ability to induce pyroptosis. No effect on protein expression. No effect on cleavage by CASP4. | ||||
Sequence: I → N | ||||||
Mutagenesis | 122 | No effect on oligomerization. | ||||
Sequence: C → A | ||||||
Mutagenesis | 138 | Complete loss of homooligomerization, lipid-binding, relocalization of Gasdermin-D, N-terminal to the plasma membrane and pyroptosis, as well as loss of bactericidal activity; when associated with A-146; A-152 and A-154. Partial loss of homooligomerization and pyroptosis; when associated with A-146. | ||||
Sequence: R → A or S | ||||||
Mutagenesis | 146 | Complete loss of homooligomerization, lipid-binding, relocalization of Gasdermin-D, N-terminal to the plasma membrane and pyroptosis, as well as loss of bactericidal activity; when associated with A-138 or with S-138; A-152 and A-154. Partial loss of homooligomerization and pyroptosis; when associated with A-138, with A-152 or with A-152 and A-154. | ||||
Sequence: K → A | ||||||
Mutagenesis | 152 | Complete loss of homooligomerization, lipid-binding, relocalization of Gasdermin-D, N-terminal to the plasma membrane and pyroptosis, as well as loss of bactericidal activity; when associated with A-138 or with S-138; A-146 and A-154. Partial loss of homooligomerization and pyroptosis; when associated with A-146 or with A-154, or with A-146 and A-154. | ||||
Sequence: R → A | ||||||
Mutagenesis | 154 | Complete loss of homooligomerization, lipid-binding, relocalization of Gasdermin-D, N-terminal to the plasma membrane and pyroptosis, as well as loss of bactericidal activity; when associated with A-138 or with S-138; A-146 and A-152. Partial loss of homooligomerization and pyroptosis; when associated with A-152 or with A-146 and A-152. | ||||
Sequence: R → A | ||||||
Mutagenesis | 192 | Loss of oligomerization of Gasdermin-D, N-terminal. Abolished palmitoylation and ability to form a pore and mediate pyroptosis. | ||||
Sequence: C → A | ||||||
Mutagenesis | 193 | Reduced homoolimerization, leading to reduced ability to induce pyroptosis. | ||||
Sequence: L → D | ||||||
Mutagenesis | 230-233 | Reduced homoolimerization, leading to reduced ability to induce pyroptosis. | ||||
Sequence: ILLV → ALLA | ||||||
Mutagenesis | 237 | No effect on pyroptosis; when associated with A-239 or with A-239; A-248 and A-249. | ||||
Sequence: K → A | ||||||
Mutagenesis | 239 | No effect on pyroptosis; when associated with A-237 or with A-237; A-248 and A-249. | ||||
Sequence: R → A | ||||||
Mutagenesis | 248 | No effect on pyroptosis; when associated with A-237; A-239 and A-249. | ||||
Sequence: R → A | ||||||
Mutagenesis | 249 | No effect on pyroptosis; when associated with A-237; A-239 and A-248. | ||||
Sequence: K → A | ||||||
Mutagenesis | 265 | No effect on oligomerization. | ||||
Sequence: C → A | ||||||
Mutagenesis | 273 | Impaired interaction and cleavage by CASP1. | ||||
Sequence: L → A | ||||||
Mutagenesis | 276 | Loss of CASP1-induced cleavage, pyroptosis and IL1B release. Does not impair interaction with CASP1. Loss of CASP4/CASP11-induced cleavage. Abolished ability to induce pyroptosis following inactivation of MAP3K7/TAK1 by Yersinia toxin YopJ. | ||||
Sequence: D → A or N | ||||||
Mutagenesis | 292 | Disrupts intramolecular interactions and autoinhibition, leading to spontaneous pyroptosis-inducing activity. | ||||
Sequence: L → D | ||||||
Mutagenesis | 295 | Disrupts intramolecular interactions and autoinhibition, leading to spontaneous pyroptosis-inducing activity. | ||||
Sequence: E → R | ||||||
Mutagenesis | 306-310 | In 5A mutant; abolished interaction with CASP1; when associated with 361-L--L370. | ||||
Sequence: LEMEL → AEMEA | ||||||
Mutagenesis | 309-313 | Abolished generation of the Gasdermin-D, p40 chain and ability to promote secretion of IL33. | ||||
Sequence: ELRQQ → AAAAA | ||||||
Mutagenesis | 309-313 | Abolished generation of the Gasdermin-D, p40 chain and ability to promote secretion of IL33. | ||||
Sequence: Missing | ||||||
Mutagenesis | 361-370 | In 5A mutant; abolished interaction with CASP1; when associated with 306-L--L310. | ||||
Sequence: LDSGELVPEL → ADSGELAPEA | ||||||
Mutagenesis | 369 | Impaired interaction and cleavage by CASP1. | ||||
Sequence: E → K | ||||||
Mutagenesis | 376 | Spontaneous pyroptosis-inducing activity. | ||||
Sequence: Y → D | ||||||
Mutagenesis | 380 | Disrupts intramolecular interactions and autoinhibition, leading to spontaneous pyroptosis-inducing activity. | ||||
Sequence: A → D | ||||||
Mutagenesis | 470 | Disrupts intramolecular interactions and autoinhibition, leading to spontaneous pyroptosis-inducing activity. | ||||
Sequence: S → R | ||||||
Mutagenesis | 474 | Disrupts intramolecular interactions and autoinhibition, leading to spontaneous pyroptosis-inducing activity. | ||||
Sequence: A → D |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 36 variants from UniProt as well as other sources including ClinVar and dbSNP.
Chemistry
PTM/Processing
Features
Showing features for chain, modified residue, lipidation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000459019 | 1-88 | Gasdermin-D, p13 | |||
Sequence: MPSAFEKVVKNVIKEVSGSRGDLIPVDSLRNSTSFRPYCLLNRKFSSSRFWKPRYSCVNLSIKDILEPSAPEPEPECFGSFKVSDVVD | ||||||
Chain | PRO_0000437528 | 1-276 | Gasdermin-D, N-terminal | |||
Sequence: MPSAFEKVVKNVIKEVSGSRGDLIPVDSLRNSTSFRPYCLLNRKFSSSRFWKPRYSCVNLSIKDILEPSAPEPEPECFGSFKVSDVVDGNIQGRVMLSGMGEGKISGGAAVSDSSSASMNVCILRVTQKTWETMQHERHLQQPENKILQQLRSRGDDLFVVTEVLQTKEEVQITEVHSQEGSGQFTLPGALCLKGEGKGHQSRKKMVTIPAGSILAFRVAQLLIGSKWDILLVSDEKQRTFEPSSGDRKAVGQRHHGLNVLAALCSIGKQLSLLSD | ||||||
Chain | PRO_0000459020 | 1-310 | Gasdermin-D, p40 | |||
Sequence: MPSAFEKVVKNVIKEVSGSRGDLIPVDSLRNSTSFRPYCLLNRKFSSSRFWKPRYSCVNLSIKDILEPSAPEPEPECFGSFKVSDVVDGNIQGRVMLSGMGEGKISGGAAVSDSSSASMNVCILRVTQKTWETMQHERHLQQPENKILQQLRSRGDDLFVVTEVLQTKEEVQITEVHSQEGSGQFTLPGALCLKGEGKGHQSRKKMVTIPAGSILAFRVAQLLIGSKWDILLVSDEKQRTFEPSSGDRKAVGQRHHGLNVLAALCSIGKQLSLLSDGIDEEELIEAADFQGLYAEVKACSSELESLEMEL | ||||||
Chain | PRO_0000148176 | 1-487 | Gasdermin-D | |||
Sequence: MPSAFEKVVKNVIKEVSGSRGDLIPVDSLRNSTSFRPYCLLNRKFSSSRFWKPRYSCVNLSIKDILEPSAPEPEPECFGSFKVSDVVDGNIQGRVMLSGMGEGKISGGAAVSDSSSASMNVCILRVTQKTWETMQHERHLQQPENKILQQLRSRGDDLFVVTEVLQTKEEVQITEVHSQEGSGQFTLPGALCLKGEGKGHQSRKKMVTIPAGSILAFRVAQLLIGSKWDILLVSDEKQRTFEPSSGDRKAVGQRHHGLNVLAALCSIGKQLSLLSDGIDEEELIEAADFQGLYAEVKACSSELESLEMELRQQILVNIGKILQDQPSMEALEASLGQGLCSGGQVEPLDGPAGCILECLVLDSGELVPELAAPIFYLLGALAVLSETQQQLLAKALETTVLSKQLELVKHVLEQSTPWQEQSSVSLPTVLLGDCWDEKNPTWVLLEECGLRLQVESPQVHWEPTSLIPTSALYASLFLLSSLGQKPC | ||||||
Modified residue | 38 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Modified residue | 39 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 57 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 77 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 122 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 192 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Lipidation | 192 | S-palmitoyl cysteine | ||||
Sequence: C | ||||||
Modified residue | 265 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Chain | PRO_0000437529 | 277-487 | Gasdermin-D, C-terminal | |||
Sequence: GIDEEELIEAADFQGLYAEVKACSSELESLEMELRQQILVNIGKILQDQPSMEALEASLGQGLCSGGQVEPLDGPAGCILECLVLDSGELVPELAAPIFYLLGALAVLSETQQQLLAKALETTVLSKQLELVKHVLEQSTPWQEQSSVSLPTVLLGDCWDEKNPTWVLLEECGLRLQVESPQVHWEPTSLIPTSALYASLFLLSSLGQKPC | ||||||
Modified residue | 299 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 434 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 487 | S-(2-succinyl)cysteine | ||||
Sequence: C |
Post-translational modification
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).
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).
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).
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.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Highly expressed in brain endothelial cells.
Developmental stage
Expression starts at 8.5 dpc and increases from 13.5 dpc on. Still detected after birth.
Gene expression databases
Interaction
Subunit
Gasdermin-D, N-terminal
Homooligomer; homooligomeric ring-shaped pore complex containing 27-28 subunits when inserted in the membrane (PubMed:34289345).
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 (PubMed:26611636).
Although this recruitment is also observed in the absence of PYCARD, it is more efficient in its presence (PubMed:26611636).
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 (PubMed:26611636).
Although this recruitment is also observed in the absence of PYCARD, it is more efficient in its presence (PubMed:26611636).
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 278-298 | Linker helix loop | ||||
Sequence: IDEEELIEAADFQGLYAEVKA |
Domain
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).
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.
Sequence similarities
Belongs to the gasdermin family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length487
- Mass (Da)53,238
- Last updated2001-06-01 v1
- Checksum6702C95B0F92BC49
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A2R8VKQ7 | A0A2R8VKQ7_MOUSE | Gsdmd | 263 | ||
A0A2R8W727 | A0A2R8W727_MOUSE | Gsdmd | 57 |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AK007710 EMBL· GenBank· DDBJ | BAB25204.1 EMBL· GenBank· DDBJ | mRNA | ||
AK165858 EMBL· GenBank· DDBJ | BAE38418.1 EMBL· GenBank· DDBJ | mRNA | ||
AK171294 EMBL· GenBank· DDBJ | BAE42374.1 EMBL· GenBank· DDBJ | mRNA | ||
BC029813 EMBL· GenBank· DDBJ | AAH29813.1 EMBL· GenBank· DDBJ | mRNA |