ID GSDMD_MOUSE Reviewed; 487 AA. AC Q9D8T2; Q3TBD9; DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 02-DEC-2020, entry version 124. DE RecName: Full=Gasdermin-D {ECO:0000303|PubMed:26611636}; DE AltName: Full=Gasdermin domain-containing protein 1; DE Contains: DE RecName: Full=Gasdermin-D, N-terminal {ECO:0000305}; DE Short=GSDMD-NT {ECO:0000303|PubMed:27383986}; DE Short=mGSDMD-NTD {ECO:0000303|PubMed:31097341}; DE Short=p30 {ECO:0000303|PubMed:27339137}; DE Contains: DE RecName: Full=Gasdermin-D, C-terminal {ECO:0000305}; DE Short=GSDMD-CT {ECO:0000303|PubMed:27383986}; DE Short=mGSDMD-CTD {ECO:0000303|PubMed:31097341}; DE Short=p20 {ECO:0000303|PubMed:27339137}; GN Name=Gsdmd {ECO:0000303|PubMed:26611636, ECO:0000312|MGI:MGI:1916396}; GN Synonyms=Gsdmdc1; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J, and NOD; TISSUE=Lung, and Pancreas; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=FVB/N; TISSUE=Liver; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP PROTEIN SEQUENCE OF 11-44; 84-125; 139-152 AND 204-218, FUNCTION, RP ASSOCIATION WITH NLRP3 INFLAMMASOME, SUBCELLULAR LOCATION, MASS RP SPECTROMETRY, MUTAGENESIS OF ASP-276, AND CLEAVAGE BY CASP1. RX PubMed=26611636; DOI=10.1038/cr.2015.139; RA He W.T., Wan H., Hu L., Chen P., Wang X., Huang Z., Yang Z.H., Zhong C.Q., RA Han J.; RT "Gasdermin D is an executor of pyroptosis and required for interleukin- RT 1beta secretion."; RL Cell Res. 25:1285-1298(2015). RN [4] RP PROTEIN SEQUENCE OF 277-288, FUNCTION, DISRUPTION PHENOTYPE, MUTAGENESIS OF RP ILE-105 AND ASP-276, AND CLEAVAGE BY CASP1 AND CASP4. RX PubMed=26375259; DOI=10.1038/nature15541; RA Kayagaki N., Stowe I.B., Lee B.L., O'Rourke K., Anderson K., Warming S., RA Cuellar T., Haley B., Roose-Girma M., Phung Q.T., Liu P.S., Lill J.R., RA Li H., Wu J., Kummerfeld S., Zhang J., Lee W.P., Snipas S.J., RA Salvesen G.S., Morris L.X., Fitzgerald L., Zhang Y., Bertram E.M., RA Goodnow C.C., Dixit V.M.; RT "Caspase-11 cleaves gasdermin D for non-canonical inflammasome RT signalling."; RL Nature 526:666-671(2015). RN [5] RP DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE. RX PubMed=18693275; DOI=10.1002/dvg.20412; RA Fujii T., Tamura M., Tanaka S., Kato Y., Yamamoto H., Mizushina Y., RA Shiroishi T.; RT "Gasdermin D (Gsdmd) is dispensable for mouse intestinal epithelium RT development."; RL Genesis 46:418-423(2008). RN [6] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver, Lung, and Spleen; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [7] RP FUNCTION, DISRUPTION PHENOTYPE, AND ACTIVITY REGULATION. RX PubMed=26375003; DOI=10.1038/nature15514; RA Shi J., Zhao Y., Wang K., Shi X., Wang Y., Huang H., Zhuang Y., Cai T., RA Wang F., Shao F.; RT "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell RT death."; RL Nature 526:660-665(2015). RN [8] RP FUNCTION (GASDERMIN-D, N-TERMINAL), SUBCELLULAR LOCATION, AND ACTIVATION RP WITH NLRC4 INFLAMMASOME. RX PubMed=27418190; DOI=10.15252/embj.201694696; RA Sborgi L., Ruehl S., Mulvihill E., Pipercevic J., Heilig R., Stahlberg H., RA Farady C.J., Mueller D.J., Broz P., Hiller S.; RT "GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell RT death."; RL EMBO J. 35:1766-1778(2016). RN [9] RP FUNCTION. RX PubMed=27385778; DOI=10.4049/jimmunol.1600699; RA Russo H.M., Rathkey J., Boyd-Tressler A., Katsnelson M.A., Abbott D.W., RA Dubyak G.R.; RT "Active caspase-1 induces plasma membrane pores that precede pyroptotic RT lysis and are blocked by lanthanides."; RL J. Immunol. 197:1353-1367(2016). RN [10] RP FUNCTION (GASDERMIN-D, N-TERMINAL), CLEAVAGE BY CASP4, LIPID-BINDING, RP HOMOOLIGOMERIZATION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-39; RP CYS-57; CYS-77; CYS-122; ARG-138; LYS-146; ARG-152; ARG-154; CYS-192; RP LYS-237; ARG-239; ARG-248; LYS-249 AND CYS-265. RX PubMed=27383986; DOI=10.1038/nature18629; RA Liu X., Zhang Z., Ruan J., Pan Y., Magupalli V.G., Wu H., Lieberman J.; RT "Inflammasome-activated gasdermin D causes pyroptosis by forming membrane RT pores."; RL Nature 535:153-158(2016). RN [11] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27339137; DOI=10.1073/pnas.1607769113; RA Aglietti R.A., Estevez A., Gupta A., Ramirez M.G., Liu P.S., Kayagaki N., RA Ciferri C., Dixit V.M., Dueber E.C.; RT "GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in RT membranes."; RL Proc. Natl. Acad. Sci. U.S.A. 113:7858-7863(2016). RN [12] RP FUNCTION, PROTEOLYTIC CLEAVAGE, AND ACTIVITY REGULATION. RX PubMed=30381458; DOI=10.1073/pnas.1809548115; RA Sarhan J., Liu B.C., Muendlein H.I., Li P., Nilson R., Tang A.Y., RA Rongvaux A., Bunnell S.C., Shao F., Green D.R., Poltorak A.; RT "Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during RT Yersinia infection."; RL Proc. Natl. Acad. Sci. U.S.A. 115:E10888-E10897(2018). RN [13] RP FUNCTION, PROTEOLYTIC CLEAVAGE, ACTIVITY REGULATION, AND MUTAGENESIS OF RP ASP-276. RX PubMed=30361383; DOI=10.1126/science.aau2818; RA Orning P., Weng D., Starheim K., Ratner D., Best Z., Lee B., Brooks A., RA Xia S., Wu H., Kelliher M.A., Berger S.B., Gough P.J., Bertin J., RA Proulx M.M., Goguen J.D., Kayagaki N., Fitzgerald K.A., Lien E.; RT "Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of RT gasdermin D and cell death."; RL Science 362:1064-1069(2018). RN [14] RP ACTIVITY REGULATION, AND PROTEOLYTIC CLEAVAGE. RX PubMed=32554464; DOI=10.1074/jbc.ra120.014259; RA Bibo-Verdugo B., Snipas S.J., Kolt S., Poreba M., Salvesen G.S.; RT "Extended subsite profiling of the pyroptosis effector protein gasdermin D RT reveals a region recognized by inflammatory caspase-11."; RL J. Biol. Chem. 295:11292-11302(2020). RN [15] RP FUNCTION, SUCCINATION AT CYS-39; CYS-57; CYS-77; CYS-122; CYS-192; CYS-265; RP CYS-299; CYS-434 AND CYS-487, AND MUTAGENESIS OF CYS-192. RX PubMed=32820063; DOI=10.1126/science.abb9818; RA Humphries F., Shmuel-Galia L., Ketelut-Carneiro N., Li S., Wang B., RA Nemmara V.V., Wilson R., Jiang Z., Khalighinejad F., Muneeruddin K., RA Shaffer S.A., Dutta R., Ionete C., Pesiridis S., Yang S., Thompson P.R., RA Fitzgerald K.A.; RT "Succination inactivates gasdermin D and blocks pyroptosis."; RL Science 0:0-0(2020). RN [16] {ECO:0000244|PDB:6AO3} RP X-RAY CRYSTALLOGRAPHY (1.76 ANGSTROMS) OF 277-487, ACTIVITY REGULATION, RP DOMAIN, AND MUTAGENESIS OF ILE-105 AND TYR-376. RX PubMed=29576317; DOI=10.1016/j.str.2018.03.002; RA Liu Z., Wang C., Rathkey J.K., Yang J., Dubyak G.R., Abbott D.W., RA Xiao T.S.; RT "Structures of the Gasdermin D C-terminal domains reveal mechanisms of RT autoinhibition."; RL Structure 26:778-784(2018). RN [17] {ECO:0000244|PDB:6N9N} RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS), ACTIVITY REGULATION, DOMAIN, AND RP MUTAGENESIS OF 7-LYS--LYS-14; LEU-29; 43-ARG--ARG-54; 50-PHE-TRP-51; RP LEU-60; PHE-81; ILE-91; VAL-95; LEU-193; 230-ILE--VAL-233; LEU-292; RP GLU-295; ALA-380; SER-470 AND ALA-474. RX PubMed=31097341; DOI=10.1016/j.immuni.2019.04.017; RA Liu Z., Wang C., Yang J., Zhou B., Yang R., Ramachandran R., Abbott D.W., RA Xiao T.S.; RT "Crystal structures of the full-length murine and human Gasdermin D reveal RT mechanisms of autoinhibition, lipid binding, and oligomerization."; RL Immunity 51:43-49(2019). RN [18] {ECO:0000244|PDB:6KMV} RP X-RAY CRYSTALLOGRAPHY (3.35 ANGSTROMS) OF 287-484 AND 289-484 IN COMPLEX RP WITH GSDMD. RX PubMed=32109412; DOI=10.1016/j.cell.2020.02.002; RA Wang K., Sun Q., Zhong X., Zeng M., Zeng H., Shi X., Li Z., Wang Y., RA Zhao Q., Shao F., Ding J.; RT "Structural mechanism for GSDMD targeting by autoprocessed caspases in RT pyroptosis."; RL Cell 180:941-955(2020). RN [19] {ECO:0000244|PDB:6VIE} RP X-RAY CRYSTALLOGRAPHY (3.40 ANGSTROMS) IN COMPLEX WITH CASP1, PROTEOLYTIC RP CLEAVAGE, ACTIVITY REGULATION, AND MUTAGENESIS OF LEU-273; ASP-276; RP 306-LEU--LEU-310; 361-LEU--LEU-370 AND GLU-369. RX PubMed=32553275; DOI=10.1016/j.immuni.2020.06.007; RA Liu Z., Wang C., Yang J., Chen Y., Zhou B., Abbott D.W., Xiao T.S.; RT "Caspase-1 engages full-length Gasdermin D through two distinct interfaces RT that mediate caspase recruitment and substrate cleavage."; RL Immunity 53:106-114(2020). CC -!- FUNCTION: [Gasdermin-D]: Precursor of a pore-forming protein that plays CC a key role in host defense against pathogen infection and danger CC signals (PubMed:26375003, PubMed:26375259, PubMed:26611636, CC PubMed:27383986, PubMed:27385778, PubMed:27418190). This form CC constitutes the precursor of the pore-forming protein: upon cleavage, CC the released N-terminal moiety (Gasdermin-D, N-terminal) binds to CC membranes and forms pores, triggering pyroptosis (PubMed:26375003, CC PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, CC PubMed:27418190). {ECO:0000269|PubMed:26375003, CC ECO:0000269|PubMed:26375259, ECO:0000269|PubMed:26611636, CC ECO:0000269|PubMed:27383986, ECO:0000269|PubMed:27385778, CC ECO:0000269|PubMed:27418190}. CC -!- FUNCTION: [Gasdermin-D, N-terminal]: Promotes pyroptosis in response to CC microbial infection and danger signals (PubMed:26375003, CC PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, CC PubMed:27418190, PubMed:32820063). Produced by the cleavage of CC gasdermin-D by inflammatory caspases CASP1 or CASP4/CASP11 in response CC to canonical, as well as non-canonical (such as cytosolic LPS) CC inflammasome activators (PubMed:26375003, PubMed:26375259, CC PubMed:26611636, PubMed:27383986, PubMed:27385778, PubMed:27418190). CC After cleavage, moves to the plasma membrane where it strongly binds to CC inner leaflet lipids, including monophosphorylated CC phosphatidylinositols, such as phosphatidylinositol 4-phosphate, CC bisphosphorylated phosphatidylinositols, such as phosphatidylinositol CC (4,5)-bisphosphate, as well as phosphatidylinositol (3,4,5)- CC bisphosphate, and more weakly to phosphatidic acid and CC phosphatidylserine (PubMed:27383986, PubMed:27339137). Homooligomerizes CC within the membrane and forms pores of 10-15 nanometers (nm) of inner CC diameter, allowing the release of mature IL1B and triggering pyroptosis CC (PubMed:27383986). Exhibits bactericidal activity (PubMed:27383986). CC Gasdermin-D, N-terminal released from pyroptotic cells into the CC extracellular milieu rapidly binds to and kills both Gram-negative and CC Gram-positive bacteria, without harming neighboring mammalian cells, as CC it does not disrupt the plasma membrane from the outside due to lipid- CC binding specificity (PubMed:27383986). Under cell culture conditions, CC also active against intracellular bacteria, such as Listeria CC monocytogenes (PubMed:27383986). Also active in response to MAP3K7/TAK1 CC inactivation by Yersinia toxin YopJ, which triggers cleavage by CASP8 CC and subsequent activation (PubMed:30361383, PubMed:30381458). Strongly CC binds to bacterial and mitochondrial lipids, including cardiolipin. CC Does not bind to unphosphorylated phosphatidylinositol, CC phosphatidylethanolamine nor phosphatidylcholine (PubMed:27383986). CC {ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:26375259, CC ECO:0000269|PubMed:26611636, ECO:0000269|PubMed:27339137, CC ECO:0000269|PubMed:27383986, ECO:0000269|PubMed:27385778, CC ECO:0000269|PubMed:27418190, ECO:0000269|PubMed:30361383, CC ECO:0000269|PubMed:30381458, ECO:0000269|PubMed:32820063}. CC -!- ACTIVITY REGULATION: [Gasdermin-D]: The full-length protein before CC cleavage is inactive: intramolecular interactions between N- and C- CC terminal domains mediate autoinhibition in the absence of activation CC signal (PubMed:26375003, PubMed:26375259, PubMed:26611636, CC PubMed:29576317, PubMed:31097341). The intrinsic pyroptosis-inducing CC activity is carried by the released N-terminal moiety (Gasdermin-D, N- CC terminal) following cleavage by inflammatory caspases CASP1, CC CASP4/CASP11 or CASP8 (PubMed:26375003, PubMed:26375259, CC PubMed:26611636, PubMed:30361383, PubMed:30381458, PubMed:32554464, CC PubMed:32553275). Cleavage at Asp-88 by CASP3 or CAPS7 inactivates the CC ability to mediate pyroptosis (By similarity). CC {ECO:0000250|UniProtKB:P57764, ECO:0000269|PubMed:26375003, CC ECO:0000269|PubMed:26375259, ECO:0000269|PubMed:26611636, CC ECO:0000269|PubMed:29576317, ECO:0000269|PubMed:30361383, CC ECO:0000269|PubMed:30381458, ECO:0000269|PubMed:31097341, CC ECO:0000269|PubMed:32553275, ECO:0000269|PubMed:32554464}. CC -!- SUBUNIT: [Gasdermin-D, N-terminal]: Homooligomer; homooligomeric ring- CC shaped pore complex containing 27-28 subunits when inserted in the CC membrane (By similarity). In response to a canonical inflammasome CC stimulus, such as nigericin, recruited to NLRP3 inflammasone with CC similar kinetics to that of uncleaved CASP1 precursor CC (PubMed:26611636). Although this recruitment is also observed in the CC absence of PYCARD, it is more efficient in its presence CC (PubMed:26611636). {ECO:0000250|UniProtKB:Q5Y4Y6, CC ECO:0000269|PubMed:26611636}. CC -!- SUBCELLULAR LOCATION: [Gasdermin-D]: Cytoplasm, cytosol CC {ECO:0000269|PubMed:27383986, ECO:0000269|PubMed:27418190}. CC Inflammasome {ECO:0000269|PubMed:26611636}. Note=In response to a CC canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 CC inflammasone with similar kinetics to that of uncleaved CASP1 CC precursor. {ECO:0000269|PubMed:26611636}. CC -!- SUBCELLULAR LOCATION: [Gasdermin-D, N-terminal]: Cell membrane CC {ECO:0000269|PubMed:27339137, ECO:0000269|PubMed:27383986, CC ECO:0000269|PubMed:27418190}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:P57764}. Secreted {ECO:0000269|PubMed:27383986}. CC Note=Released in the extracellular milieu following pyroptosis. CC {ECO:0000269|PubMed:27383986}. CC -!- SUBCELLULAR LOCATION: [Gasdermin-D, C-terminal]: Cytoplasm, cytosol CC {ECO:0000305|PubMed:27339137}. CC -!- DEVELOPMENTAL STAGE: Expression starts at 8.5 dpc and increases from CC 13.5 dpc on. Still detected after birth. {ECO:0000269|PubMed:18693275}. CC -!- DOMAIN: Intramolecular interactions between N- and C-terminal domains CC mediate autoinhibition in the absence of cleavage by inflammatory CC caspases CASP1 or CASP4/CASP11 (PubMed:26375003, PubMed:26375259, CC PubMed:26611636, PubMed:29576317, PubMed:31097341). The linker helix CC loop inserts into the N-terminal domain (By similarity). The intrinsic CC pyroptosis-inducing activity is carried by Gasdermin-D, N-terminal, CC that is released upon cleavage by inflammatory caspases CC (PubMed:26375003, PubMed:26375259, PubMed:26611636). CC {ECO:0000250|UniProtKB:P57764, ECO:0000269|PubMed:26375003, CC ECO:0000269|PubMed:26375259, ECO:0000269|PubMed:26611636, CC ECO:0000269|PubMed:29576317, ECO:0000269|PubMed:31097341}. CC -!- PTM: Cleavage at Asp-276 by CASP1 (mature and uncleaved precursor CC forms), CASP4/CASP11 or CASP8 relieves autoinhibition and is sufficient CC to initiate pyroptosis (PubMed:26375259, PubMed:26611636, CC PubMed:32554464, PubMed:32553275). Cleavage by CASP1 and CASP4/CASP11 CC is not strictly dependent on the consensus cleavage site on GSDMD but CC depends on an exosite interface on CASP1 that recognizes and binds the CC Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32554464, CC PubMed:32553275). Cleavage by CASP8 takes place following inactivation CC of MAP3K7/TAK1 by Yersinia toxin YopJ (PubMed:30361383, CC PubMed:30381458). Cleavage at Asp-88 by CASP3 or CAPS7 inactivates the CC ability to mediate pyroptosis (By similarity). CC {ECO:0000250|UniProtKB:P57764, ECO:0000269|PubMed:26375259, CC ECO:0000269|PubMed:26611636, ECO:0000269|PubMed:30361383, CC ECO:0000269|PubMed:30381458, ECO:0000269|PubMed:32553275, CC ECO:0000269|PubMed:32554464}. CC -!- PTM: [Gasdermin-D]: Succination of Cys-192 by the Krebs cycle CC intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, CC inhibits processing by caspases, and ability to initiate pyroptosis CC (PubMed:32820063). Succination modification is catalyzed by a non- CC enzymatic reaction caused by an accumulation of fumarate CC (PubMed:32820063). {ECO:0000269|PubMed:32820063}. CC -!- DISRUPTION PHENOTYPE: Knockout mice are born at the expected Mendelian CC rate and do not exhibit any overt phenotype in normal housing CC conditions. The gastrointestinal tract develops normally. They are CC however resistant to LPS-induced lethal septic shock. Primary bone CC marrow-derived macrophages fail to undergo pyroptosis in response to CC canonical (acting via CASP1), as well as to non-canonical (acting via CC CASP4) inflammasome activators. CASP1-mediated IL1B release is also CC impaired, but not CASP1 autoprocessing, nor IL1B maturation. CC {ECO:0000269|PubMed:18693275, ECO:0000269|PubMed:26375003, CC ECO:0000269|PubMed:26375259}. CC -!- SIMILARITY: Belongs to the gasdermin family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK007710; BAB25204.1; -; mRNA. DR EMBL; AK165858; BAE38418.1; -; mRNA. DR EMBL; AK171294; BAE42374.1; -; mRNA. DR EMBL; BC029813; AAH29813.1; -; mRNA. DR CCDS; CCDS27551.1; -. DR RefSeq; NP_081236.1; NM_026960.4. DR PDB; 6AO3; X-ray; 1.76 A; A/B/C/D=277-487. DR PDB; 6KMV; X-ray; 3.35 A; C/G/O=287-484, D/K/S/T/W/b/f=288-484, H=294-484, L/P/e=271-484, X=286-484, a=289-484. DR PDB; 6N9N; X-ray; 3.30 A; A/B=1-487. DR PDB; 6VIE; X-ray; 3.40 A; C/D=1-487. DR PDBsum; 6AO3; -. DR PDBsum; 6KMV; -. DR PDBsum; 6N9N; -. DR PDBsum; 6VIE; -. DR SMR; Q9D8T2; -. DR DIP; DIP-61777N; -. DR IntAct; Q9D8T2; 1. DR STRING; 10090.ENSMUSP00000023238; -. DR iPTMnet; Q9D8T2; -. DR PhosphoSitePlus; Q9D8T2; -. DR SwissPalm; Q9D8T2; -. DR EPD; Q9D8T2; -. DR MaxQB; Q9D8T2; -. DR PaxDb; Q9D8T2; -. DR PeptideAtlas; Q9D8T2; -. DR PRIDE; Q9D8T2; -. DR Antibodypedia; 27909; 138 antibodies. DR Ensembl; ENSMUST00000023238; ENSMUSP00000023238; ENSMUSG00000022575. DR GeneID; 69146; -. DR KEGG; mmu:69146; -. DR UCSC; uc007whh.1; mouse. DR CTD; 79792; -. DR MGI; MGI:1916396; Gsdmd. DR eggNOG; ENOG502S0IQ; Eukaryota. DR GeneTree; ENSGT00950000183140; -. DR HOGENOM; CLU_040752_1_0_1; -. DR InParanoid; Q9D8T2; -. DR OMA; TSFQPYC; -. DR OrthoDB; 747086at2759; -. DR PhylomeDB; Q9D8T2; -. DR TreeFam; TF331886; -. DR Reactome; R-MMU-6798695; Neutrophil degranulation. DR BioGRID-ORCS; 69146; 1 hit in 17 CRISPR screens. DR PRO; PR:Q9D8T2; -. DR Proteomes; UP000000589; Chromosome 15. DR RNAct; Q9D8T2; protein. DR Bgee; ENSMUSG00000022575; Expressed in intestine and 171 other tissues. DR ExpressionAtlas; Q9D8T2; baseline and differential. DR Genevisible; Q9D8T2; MM. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0072559; C:NLRP3 inflammasome complex; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:1901612; F:cardiolipin binding; IDA:UniProtKB. DR GO; GO:0070300; F:phosphatidic acid binding; IDA:UniProtKB. DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:UniProtKB. DR GO; GO:0070273; F:phosphatidylinositol-4-phosphate binding; IDA:UniProtKB. DR GO; GO:0001786; F:phosphatidylserine binding; IDA:UniProtKB. DR GO; GO:0031668; P:cellular response to extracellular stimulus; IDA:MGI. DR GO; GO:0042742; P:defense response to bacterium; IBA:GO_Central. DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IDA:UniProtKB. DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IDA:UniProtKB. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW. DR GO; GO:0046931; P:pore complex assembly; IDA:UniProtKB. DR GO; GO:0035915; P:pore formation in membrane of other organism; IDA:UniProtKB. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:UniProtKB. DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB. DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB. DR InterPro; IPR007677; Gasdermin. DR InterPro; IPR040460; Gasdermin_pore. DR InterPro; IPR041263; Gasdermin_PUB. DR PANTHER; PTHR16399; PTHR16399; 1. DR Pfam; PF04598; Gasdermin; 1. DR Pfam; PF17708; Gasdermin_C; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Cytoplasm; Direct protein sequencing; KW Immunity; Inflammasome; Inflammatory response; Innate immunity; KW Lipid-binding; Membrane; Necrosis; Phosphoprotein; Reference proteome; KW Secreted; Transmembrane; Transmembrane beta strand. FT CHAIN 1..487 FT /note="Gasdermin-D" FT /id="PRO_0000148176" FT CHAIN 1..276 FT /note="Gasdermin-D, N-terminal" FT /evidence="ECO:0000305|PubMed:27383986, FT ECO:0000305|PubMed:32553275" FT /id="PRO_0000437528" FT CHAIN 277..487 FT /note="Gasdermin-D, C-terminal" FT /evidence="ECO:0000305|PubMed:27383986, FT ECO:0000305|PubMed:32553275" FT /id="PRO_0000437529" FT REGION 278..298 FT /note="Linker helix loop" FT /evidence="ECO:0000250|UniProtKB:P57764" FT SITE 88..89 FT /note="Cleavage; by CASP3" FT /evidence="ECO:0000250|UniProtKB:P57764" FT SITE 276..277 FT /note="Cleavage; by caspases CASP1, CASP4/CASP11 and CASP8" FT /evidence="ECO:0000269|PubMed:26375259, FT ECO:0000269|PubMed:30361383, ECO:0000269|PubMed:32553275" FT MOD_RES 38 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P57764" FT MOD_RES 39 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 57 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 77 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 122 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 192 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 265 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 299 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 434 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 487 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MUTAGEN 7..14 FT /note="KVVKNVIK->AVVANVIA: Reduced ability to induct FT pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 29 FT /note="L->A: Reduced homoolimerization, leading to reduced FT ability to induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 39 FT /note="C->A: Loss of oligomerization of Gasdermin-D, N- FT terminal." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 43..54 FT /note="RKFSSSRFWKPR->AAFSSSRFWAPA: Reduced ability to FT induct pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 50..51 FT /note="FW->GG: RKFSSSRFWKPR." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 57 FT /note="C->A: No effect on oligomerization." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 60 FT /note="L->G: Reduced homoolimerization, leading to reduced FT ability to induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 77 FT /note="C->A: No effect on oligomerization." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 81 FT /note="F->D: Reduced homoolimerization, leading to reduced FT ability to induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 91 FT /note="I->D: Reduced homoolimerization, leading to reduced FT ability to induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 95 FT /note="V->D: Reduced homoolimerization, leading to reduced FT ability to induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 105 FT /note="I->N: Reduced ability to induce pyroptosis. No FT effect on protein expression. No effect on cleavage by FT CASP4." FT /evidence="ECO:0000269|PubMed:26375259, FT ECO:0000269|PubMed:29576317" FT MUTAGEN 122 FT /note="C->A: No effect on oligomerization." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 138 FT /note="R->A,S: Complete loss of homooligomerization, lipid- FT binding, relocalization of Gasdermin-D, N-terminal to the FT plasma membrane and pyroptosis, as well as loss of FT bactericidal activity; when associated with A-146; A-152 FT and A-154. Partial loss of homooligomerization and FT pyroptosis; when associated with A-146." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 146 FT /note="K->A: Complete loss of homooligomerization, lipid- FT binding, relocalization of Gasdermin-D, N-terminal to the FT plasma membrane and pyroptosis, as well as loss of FT bactericidal activity; when associated with A-138 or with FT S-138; A-152 and A-154. Partial loss of homooligomerization FT and pyroptosis; when associated with A-138, with A-152 or FT with A-152 and A-154." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 152 FT /note="R->A: Complete loss of homooligomerization, lipid- FT binding, relocalization of Gasdermin-D, N-terminal to the FT plasma membrane and pyroptosis, as well as loss of FT bactericidal activity; when associated with A-138 or with FT S-138; A-146 and A-154. Partial loss of homooligomerization FT and pyroptosis; when associated with A-146 or with A-154, FT or with A-146 and A-154." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 154 FT /note="R->A: Complete loss of homooligomerization, lipid- FT binding, relocalization of Gasdermin-D, N-terminal to the FT plasma membrane and pyroptosis, as well as loss of FT bactericidal activity; when associated with A-138 or with FT S-138; A-146 and A-152. Partial loss of homooligomerization FT and pyroptosis; when associated with A-152 or with A-146 FT and A-152." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 192 FT /note="C->A: Loss of oligomerization of Gasdermin-D, N- FT terminal." FT /evidence="ECO:0000269|PubMed:27383986, FT ECO:0000269|PubMed:32820063" FT MUTAGEN 193 FT /note="L->D: Reduced homoolimerization, leading to reduced FT ability to induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 230..233 FT /note="ILLV->ALLA: Reduced homoolimerization, leading to FT reduced ability to induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 237 FT /note="K->A: No effect on pyroptosis; when associated with FT A-239 or with A-239; A-248 and A-249." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 239 FT /note="R->A: No effect on pyroptosis; when associated with FT A-237 or with A-237; A-248 and A-249." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 248 FT /note="R->A: No effect on pyroptosis; when associated with FT A-237; A-239 and A-249." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 249 FT /note="K->A: No effect on pyroptosis; when associated with FT A-237; A-239 and A-248." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 265 FT /note="C->A: No effect on oligomerization." FT /evidence="ECO:0000269|PubMed:27383986" FT MUTAGEN 273 FT /note="L->A: Impaired interaction and cleavage by CASP1." FT /evidence="ECO:0000269|PubMed:32553275" FT MUTAGEN 276 FT /note="D->A,N: Loss of CASP1-induced cleavage, pyroptosis FT and IL1B release. Does not impair interaction with CASP1. FT Abolished ability to induce pyroptosis following FT inactivation of MAP3K7/TAK1 by Yersinia toxin YopJ." FT /evidence="ECO:0000269|PubMed:26375259, FT ECO:0000269|PubMed:26611636, ECO:0000269|PubMed:30361383, FT ECO:0000269|PubMed:32553275" FT MUTAGEN 292 FT /note="L->D: Disrupts intramolecular interactions and FT autoinhibition, leading to spontaneous pyroptosis-inducing FT activity." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 295 FT /note="E->R: Disrupts intramolecular interactions and FT autoinhibition, leading to spontaneous pyroptosis-inducing FT activity." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 306..310 FT /note="LEMEL->AEMEA: In 5A mutant; abolished interaction FT with CASP1; when associated with 361-L--L370." FT /evidence="ECO:0000269|PubMed:32553275" FT MUTAGEN 361..370 FT /note="LDSGELVPEL->ADSGELAPEA: In 5A mutant; abolished FT interaction with CASP1; when associated with 306-L--L310." FT /evidence="ECO:0000269|PubMed:32553275" FT MUTAGEN 369 FT /note="E->K: Impaired interaction and cleavage by CASP1." FT /evidence="ECO:0000269|PubMed:32553275" FT MUTAGEN 376 FT /note="Y->D: Spontaneous pyroptosis-inducing activity." FT /evidence="ECO:0000269|PubMed:29576317" FT MUTAGEN 380 FT /note="A->D: Disrupts intramolecular interactions and FT autoinhibition, leading to spontaneous pyroptosis-inducing FT activity." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 470 FT /note="S->R: Disrupts intramolecular interactions and FT autoinhibition, leading to spontaneous pyroptosis-inducing FT activity." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 474 FT /note="A->D: Disrupts intramolecular interactions and FT autoinhibition, leading to spontaneous pyroptosis-inducing FT activity." FT /evidence="ECO:0000269|PubMed:31097341" FT HELIX 6..15 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 19..21 FT /evidence="ECO:0000244|PDB:6N9N" FT HELIX 32..35 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 40..43 FT /evidence="ECO:0000244|PDB:6N9N" FT TURN 63..65 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 66..68 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 87..89 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 119..125 FT /evidence="ECO:0000244|PDB:6N9N" FT HELIX 128..137 FT /evidence="ECO:0000244|PDB:6N9N" FT HELIX 148..152 FT /evidence="ECO:0000244|PDB:6N9N" FT TURN 153..155 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 157..167 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 171..173 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 207..209 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 214..223 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 225..227 FT /evidence="ECO:0000244|PDB:6N9N" FT STRAND 229..233 FT /evidence="ECO:0000244|PDB:6N9N" FT HELIX 289..304 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 308..321 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 325..341 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 350..356 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 357..359 FT /evidence="ECO:0000244|PDB:6AO3" FT STRAND 364..366 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 368..383 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 386..396 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 400..414 FT /evidence="ECO:0000244|PDB:6AO3" FT STRAND 422..424 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 428..431 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 440..446 FT /evidence="ECO:0000244|PDB:6AO3" FT TURN 447..449 FT /evidence="ECO:0000244|PDB:6AO3" FT STRAND 454..457 FT /evidence="ECO:0000244|PDB:6AO3" FT STRAND 459..461 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 463..465 FT /evidence="ECO:0000244|PDB:6AO3" FT HELIX 466..482 FT /evidence="ECO:0000244|PDB:6AO3" SQ SEQUENCE 487 AA; 53238 MW; 6702C95B0F92BC49 CRC64; MPSAFEKVVK NVIKEVSGSR GDLIPVDSLR NSTSFRPYCL LNRKFSSSRF WKPRYSCVNL SIKDILEPSA PEPEPECFGS FKVSDVVDGN IQGRVMLSGM GEGKISGGAA VSDSSSASMN VCILRVTQKT WETMQHERHL QQPENKILQQ LRSRGDDLFV VTEVLQTKEE VQITEVHSQE GSGQFTLPGA LCLKGEGKGH QSRKKMVTIP AGSILAFRVA QLLIGSKWDI LLVSDEKQRT FEPSSGDRKA VGQRHHGLNV LAALCSIGKQ LSLLSDGIDE EELIEAADFQ GLYAEVKACS SELESLEMEL RQQILVNIGK ILQDQPSMEA LEASLGQGLC SGGQVEPLDG PAGCILECLV LDSGELVPEL AAPIFYLLGA LAVLSETQQQ LLAKALETTV LSKQLELVKH VLEQSTPWQE QSSVSLPTVL LGDCWDEKNP TWVLLEECGL RLQVESPQVH WEPTSLIPTS ALYASLFLLS SLGQKPC //