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 24-JUL-2024, entry version 142. 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}; DE Contains: DE RecName: Full=Gasdermin-D, p13 {ECO:0000305}; DE AltName: Full=Gasdermin-D, 13 kDa {ECO:0000303|PubMed:37327784}; DE Short=13 kDa GSDMD {ECO:0000303|PubMed:37327784}; DE Contains: DE RecName: Full=Gasdermin-D, p40 {ECO:0000303|PubMed:35794369}; 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 (GASDERMIN-D, AND N-TERMINAL). RX PubMed=29274245; DOI=10.1002/eji.201747404; RA Heilig R., Dick M.S., Sborgi L., Meunier E., Hiller S., Broz P.; RT "The Gasdermin-D pore acts as a conduit for IL-1beta secretion in mice."; RL Eur. J. Immunol. 48:584-592(2018). RN [13] RP FUNCTION (GASDERMIN-D, AND N-TERMINAL). RX PubMed=29195811; DOI=10.1016/j.immuni.2017.11.013; RA Evavold C.L., Ruan J., Tan Y., Xia S., Wu H., Kagan J.C.; RT "The pore-forming protein gasdermin D regulates interleukin-1 secretion RT from living macrophages."; RL Immunity 48:35-44(2018). RN [14] RP PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-276. RX PubMed=30135078; DOI=10.1084/jem.20180589; RA Lee B.L., Stowe I.B., Gupta A., Kornfeld O.S., Roose-Girma M., Anderson K., RA Warming S., Zhang J., Lee W.P., Kayagaki N.; RT "Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome RT activation."; RL J. Exp. Med. 215:2279-2288(2018). RN [15] 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 [16] 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 [17] 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 [18] 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 369:1633-1637(2020). RN [19] RP FUNCTION, AND SUBUNIT. RX PubMed=34289345; DOI=10.1016/j.cell.2021.06.028; RA Evavold C.L., Hafner-Bratkovic I., Devant P., D'Andrea J.M., Ngwa E.M., RA Borsic E., Doench J.G., LaFleur M.W., Sharpe A.H., Thiagarajah J.R., RA Kagan J.C.; RT "Control of gasdermin D oligomerization and pyroptosis by the Ragulator- RT Rag-mTORC1 pathway."; RL Cell 184:4495-4511(2021). RN [20] RP FUNCTION (GASDERMIN-D, N-TERMINAL), AND MUTAGENESIS OF 50-PHE-TRP-51. RX PubMed=33883744; DOI=10.1038/s41586-021-03478-3; RA Xia S., Zhang Z., Magupalli V.G., Pablo J.L., Dong Y., Vora S.M., Wang L., RA Fu T.M., Jacobson M.P., Greka A., Lieberman J., Ruan J., Wu H.; RT "Gasdermin D pore structure reveals preferential release of mature RT interleukin-1."; RL Nature 593:607-611(2021). RN [21] RP FUNCTION. RX PubMed=35705808; DOI=10.1038/s41586-022-04825-8; RA Nozaki K., Maltez V.I., Rayamajhi M., Tubbs A.L., Mitchell J.E., RA Lacey C.A., Harvest C.K., Li L., Nash W.T., Larson H.N., McGlaughon B.D., RA Moorman N.J., Brown M.G., Whitmire J.K., Miao E.A.; RT "Caspase-7 activates ASM to repair gasdermin and perforin pores."; RL Nature 0:0-0(2022). RN [22] RP FUNCTION (GASDERMIN-D, P40), PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF RP 309-GLU--GLN-313. RX PubMed=35794369; DOI=10.1038/s41590-022-01255-6; RA Chen W., Chen S., Yan C., Zhang Y., Zhang R., Chen M., Zhong S., Fan W., RA Zhu S., Zhang D., Lu X., Zhang J., Huang Y., Zhu L., Li X., Lv D., Fu Y., RA Iv H., Ling Z., Ma L., Jiang H., Long G., Zhu J., Wu D., Wu B., Sun B.; RT "Allergen protease-activated stress granule assembly and gasdermin D RT fragmentation control interleukin-33 secretion."; RL Nat. Immunol. 23:1021-1030(2022). RN [23] RP SUBCELLULAR LOCATION, AND SUBCELLULAR LOCATION (MICROBIAL INFECTION). RX PubMed=36227980; DOI=10.1126/science.abq0132; RA Chai Q., Yu S., Zhong Y., Lu Z., Qiu C., Yu Y., Zhang X., Zhang Y., Lei Z., RA Qiang L., Li B.X., Pang Y., Qiu X.B., Wang J., Liu C.H.; RT "A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking RT ubiquitin."; RL Science 378:eabq0132-eabq0132(2022). RN [24] RP FUNCTION (GASDERMIN-D, P40), AND PROTEOLYTIC CLEAVAGE. RX PubMed=35749514; DOI=10.1126/sciimmunol.abl7209; RA Yamagishi R., Kamachi F., Nakamura M., Yamazaki S., Kamiya T., Takasugi M., RA Cheng Y., Nonaka Y., Yukawa-Muto Y., Thuy L.T.T., Harada Y., Arai T., RA Loo T.M., Yoshimoto S., Ando T., Nakajima M., Taguchi H., Ishikawa T., RA Akiba H., Miyake S., Kubo M., Iwakura Y., Fukuda S., Chen W.Y., Kawada N., RA Rudensky A., Nakae S., Hara E., Ohtani N.; RT "Gasdermin D-mediated release of IL-33 from senescent hepatic stellate RT cells promotes obesity-associated hepatocellular carcinoma."; RL Sci. Immunol. 7:eabl7209-eabl7209(2022). RN [25] RP FUNCTION (GASDERMIN-D, P13), SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, RP AND MUTAGENESIS OF 85-ASP--ASP-88. RX PubMed=37327784; DOI=10.1016/j.cell.2023.05.027; RA He K., Wan T., Wang D., Hu J., Zhou T., Tao W., Wei Z., Lu Q., Zhou R., RA Tian Z., Flavell R.A., Zhu S.; RT "Gasdermin D licenses MHCII induction to maintain food tolerance in small RT intestine."; RL Cell 0:0-0(2023). RN [26] RP FUNCTION (GASDERMIN-D, N-TERMINAL), AND SUBCELLULAR LOCATION. RX PubMed=37001519; DOI=10.1016/j.immuni.2023.03.003; RA Zhu F., Ma J., Li W., Liu Q., Qin X., Qian Y., Wang C., Zhang Y., Li Y., RA Jiang D., Wang S., Xia P.; RT "The orphan receptor Nur77 binds cytoplasmic LPS to activate the non- RT canonical NLRP3 inflammasome."; RL Immunity 56:753-767(2023). RN [27] RP MUTAGENESIS OF 17-SER--ARG-20. RX PubMed=36599845; DOI=10.1038/s41467-022-35725-0; RA Yin H., Zheng J., He Q., Zhang X., Li X., Ma Y., Liang X., Gao J., RA Kocsis B.L., Li Z., Liu X., Alto N.M., Li L., Zhang H.; RT "Insights into the GSDMB-mediated cellular lysis and its targeting by RT IpaH7.8."; RL Nat. Commun. 14:61-61(2023). RN [28] RP PALMITOYLATION AT CYS-192. RX PubMed=38599239; DOI=10.1038/s41586-024-07373-5; RA Du G., Healy L.B., David L., Walker C., El-Baba T.J., Lutomski C.A., RA Goh B., Gu B., Pi X., Devant P., Fontana P., Dong Y., Ma X., Miao R., RA Balasubramanian A., Puthenveetil R., Banerjee A., Luo H.R., Kagan J.C., RA Oh S.F., Robinson C.V., Lieberman J., Wu H.; RT "ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D."; RL Nature 0:0-0(2024). RN [29] RP FUNCTION, ACTIVITY REGULATION, TISSUE SPECIFICITY, AND DISRUPTION RP PHENOTYPE. RX PubMed=38632402; DOI=10.1038/s41586-024-07314-2; RA Wei C., Jiang W., Wang R., Zhong H., He H., Gao X., Zhong S., Yu F., RA Guo Q., Zhang L., Schiffelers L.D.J., Zhou B., Trepel M., Schmidt F.I., RA Luo M., Shao F.; RT "Brain endothelial GSDMD activation mediates inflammatory BBB breakdown."; RL Nature 0:0-0(2024). RN [30] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-192, AND MUTAGENESIS RP OF CYS-192 AND ASP-276. RX PubMed=38538834; DOI=10.1038/s41556-024-01397-9; RA Zhang N., Zhang J., Yang Y., Shan H., Hou S., Fang H., Ma M., Chen Z., RA Tan L., Xu D.; RT "A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD RT activation in pyroptosis."; RL Nat. Cell Biol. 0:0-0(2024). RN [31] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=37988464; DOI=10.1073/pnas.2315503120; RA Fattinger S.A., Maurer L., Geiser P., Bernard E.M., Enz U., Ganguillet S., RA Guel E., Kroon S., Demarco B., Mack V., Furter M., Barthel M., Pelczar P., RA Shao F., Broz P., Sellin M.E., Hardt W.D.; RT "Gasdermin D is the only Gasdermin that provides protection against acute RT Salmonella gut infection in mice."; RL Proc. Natl. Acad. Sci. U.S.A. 120:e2315503120-e2315503120(2023). RN [32] RP PALMITOYLATION, AND ACTIVITY REGULATION. RX PubMed=38324683; DOI=10.1126/sciadv.adi9284; RA Jiang X., Zhang X., Cai X., Li N., Zheng H., Tang M., Zhu J., Su K., RA Zhang R., Ye N., Peng J., Zhao M., Wu W., Yang J., Ye H.; RT "NU6300 covalently reacts with cysteine-191 of gasdermin D to block its RT cleavage and palmitoylation."; RL Sci. Adv. 10:eadi9284-eadi9284(2024). RN [33] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-192, AND MUTAGENESIS RP OF CYS-192. RX PubMed=38530158; DOI=10.1126/sciimmunol.adn1452; RA Balasubramanian A., Hsu A.Y., Ghimire L., Tahir M., Devant P., Fontana P., RA Du G., Liu X., Fabin D., Kambara H., Xie X., Liu F., Hasegawa T., Xu R., RA Yu H., Chen M., Kolakowski S., Trauger S., Larsen M.R., Wei W., Wu H., RA Kagan J.C., Lieberman J., Luo H.R.; RT "The palmitoylation of gasdermin D directs its membrane translocation and RT pore formation during pyroptosis."; RL Sci. Immunol. 9:eadn1452-eadn1452(2024). RN [34] {ECO:0007744|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 [35] {ECO:0007744|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 [36] {ECO:0007744|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 [37] {ECO:0007744|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, PubMed:34289345, PubMed:35705808, CC PubMed:37988464, PubMed:38530158, PubMed:38538834, PubMed:38632402). CC Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1 CC or CASP4/CASP11 in response to canonical, as well as non-canonical CC (such as cytosolic LPS) inflammasome activators (PubMed:26375003, CC PubMed:26375259, PubMed:26611636, PubMed:27383986, PubMed:27385778, CC PubMed:27418190, PubMed:35705808, PubMed:38632402). After cleavage, CC moves to the plasma membrane where it strongly binds to inner leaflet CC lipids, including monophosphorylated phosphatidylinositols, such as CC phosphatidylinositol 4-phosphate, bisphosphorylated CC phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, CC as well as phosphatidylinositol (3,4,5)-bisphosphate, and more weakly CC to phosphatidic acid and phosphatidylserine (PubMed:27339137, CC PubMed:27383986). Homooligomerizes within the membrane and forms pores CC of 10-15 nanometers (nm) of inner diameter, allowing the release of CC mature interleukin-1 (IL1B and IL18) and triggering pyroptosis CC (PubMed:27383986, PubMed:29195811, PubMed:29274245, PubMed:33883744, CC PubMed:38530158, PubMed:38538834). Gasdermin pores also allow the CC release of mature caspase-7 (CASP7) (PubMed:35705808). In some, but not CC all, cells types, pyroptosis is followed by pyroptotic cell death, CC which is caused by downstream activation of ninjurin-1 (NINJ1), which CC mediates membrane rupture (cytolysis) (PubMed:38632402). Also forms CC pores in the mitochondrial membrane, resulting in release of CC mitochondrial DNA (mtDNA) into the cytosol (PubMed:37001519). 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). Required CC for mucosal tissue defense against enteric pathogens (PubMed:37988464). CC Activation of the non-canonical inflammasome in brain endothelial cells CC can lead to excessive pyroptosis, leading to blood-brain barrier CC breakdown (PubMed:38632402). Strongly binds to bacterial and CC mitochondrial lipids, including cardiolipin. Does not bind to CC unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor CC phosphatidylcholine (PubMed:27383986). {ECO:0000250|UniProtKB:P57764, 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:29195811, CC ECO:0000269|PubMed:29274245, ECO:0000269|PubMed:30361383, CC ECO:0000269|PubMed:30381458, ECO:0000269|PubMed:32820063, CC ECO:0000269|PubMed:33883744, ECO:0000269|PubMed:34289345, CC ECO:0000269|PubMed:35705808, ECO:0000269|PubMed:37001519, CC ECO:0000269|PubMed:37988464, ECO:0000269|PubMed:38530158, CC ECO:0000269|PubMed:38538834, ECO:0000269|PubMed:38632402}. CC -!- FUNCTION: [Gasdermin-D, p13]: Transcription coactivator produced by the CC cleavage by CASP3 or CASP7 in the upper small intestine in response to CC dietary antigens (PubMed:37327784). Required to maintain food tolerance CC in small intestine: translocates to the nucleus and acts as a CC coactivator for STAT1 to induce the transcription of CIITA and MHC CC class II molecules, which in turn induce type 1 regulatory T (Tr1) CC cells in upper small intestine (PubMed:37327784). CC {ECO:0000269|PubMed:37327784}. CC -!- FUNCTION: [Gasdermin-D, p40]: Produced by the cleavage by papain CC allergen (PubMed:35794369). After cleavage, moves to the plasma CC membrane and homooligomerizes within the membrane and forms pores of CC 10-15 nanometers (nm) of inner diameter, allowing the specific release CC of mature interleukin-33 (IL33), promoting type 2 inflammatory immune CC response (PubMed:35749514, PubMed:35794369). CC {ECO:0000269|PubMed:35749514, ECO:0000269|PubMed:35794369}. 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:32553275, CC PubMed:32554464). Cleavage at Asp-88 by CASP3 or CASP7 inactivates the CC ability to mediate pyroptosis (By similarity). Pore formation is CC specifically inhibited by VHH(GSDMD-1) nanobody, protecting against CC excessive pyroptosis (PubMed:38632402). Inhibited by small molecule CC NU6300, which covalently reacts with Cys-191, thereby preventing CC palmitoylation and pyroptosis (PubMed:38324683). 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 ECO:0000269|PubMed:38324683, ECO:0000269|PubMed:38632402}. CC -!- SUBUNIT: [Gasdermin-D, N-terminal]: Homooligomer; homooligomeric ring- CC shaped pore complex containing 27-28 subunits when inserted in the CC membrane (PubMed:34289345). Homooligomerization is promoted by the CC mTORC1 complex in macrophages (PubMed:34289345). In response to a CC canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 CC inflammasone with 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:0000269|PubMed:26611636, CC ECO:0000269|PubMed:34289345}. 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, ECO:0000269|PubMed:38530158, CC ECO:0000269|PubMed:38538834}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:P57764}. Secreted {ECO:0000269|PubMed:27383986}. CC Mitochondrion membrane {ECO:0000269|PubMed:37001519}. Note=Released in CC the extracellular milieu following pyroptosis (PubMed:27383986). CC Mitochondrial localization results in release of mitochondrial DNA into CC the cytosol (PubMed:37001519). {ECO:0000269|PubMed:27383986, CC ECO:0000269|PubMed:37001519}. CC -!- SUBCELLULAR LOCATION: [Gasdermin-D, N-terminal]: Cytoplasm, cytosol CC {ECO:0000269|PubMed:36227980}. Note=(Microbial infection) Upon CC infection by M.tuberculosis, localization to cell membrane is prevented CC by M.tuberculosis phosphatase PtpB that catalyzes dephosphorylation of CC phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol 4- CC phosphate, thereby inhibiting the membrane targeting of Gasdermin-D, N- CC terminal and subsequent cytokine release and pyroptosis. CC {ECO:0000269|PubMed:36227980}. CC -!- SUBCELLULAR LOCATION: [Gasdermin-D, p13]: Nucleus CC {ECO:0000269|PubMed:37327784}. CC -!- SUBCELLULAR LOCATION: [Gasdermin-D, C-terminal]: Cytoplasm, cytosol CC {ECO:0000305|PubMed:27339137}. CC -!- TISSUE SPECIFICITY: Highly expressed in brain endothelial cells. CC {ECO:0000269|PubMed:38632402}. 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 -!- DOMAIN: [Gasdermin-D, N-terminal]: Forms a ring-shaped pore complex CC containing 27-28 subunits that inserts into the membrane. The pore CC conduit is predominantly negatively charged, facilitating the release CC of mature interleukin-1 (IL1B and IL18). In contrast interleukin-1 CC precursors are not released, due to the presence of an acidic region CC that is proteolytically removed by CASP1 during maturation. CC {ECO:0000250|UniProtKB:P57764}. 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:32553275, PubMed:32554464). 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:32553275, CC PubMed:32554464). 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 CASP7 inactivates the CC ability to mediate pyroptosis, but generates the Gasdermin-D, p13 CC chain, which translocates to the nucleus and acts as a transcription CC regulator (PubMed:37327784). Cleavage by papain allergen generates the CC Gasdermin-D, p40 chain (PubMed:35794369). 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, ECO:0000269|PubMed:35794369, CC ECO:0000269|PubMed:37327784}. CC -!- PTM: [Gasdermin-D]: Palmitoylated at Cys-192 by ZDHHC5 and ZDHHC9 in CC response to microbial infection and danger signals (PubMed:38324683, CC PubMed:38530158, PubMed:38599239). May also be palmitoylated by ZDHHC7 CC (PubMed:38538834). Palmitoylation takes place before cleavage by CC caspases (CASP1, CASP4, CASP5 or CASP8) and is required for membrane CC translocation and pore formation (PubMed:38324683, PubMed:38530158, CC PubMed:38538834, PubMed:38599239). Depalmitoylated by LYPLA2 CC (PubMed:38538834). {ECO:0000269|PubMed:38324683, CC ECO:0000269|PubMed:38530158, ECO:0000269|PubMed:38538834, CC ECO:0000269|PubMed:38599239}. 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 -!- PTM: Glycosylated: O-GlcNAcylation by OGT leads to reduced cleavage by CC CASP4 and decreased LPS-induced endothelial cell pyroptosis. CC {ECO:0000250|UniProtKB:P57764}. 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 (PubMed:18693275, PubMed:26375003, PubMed:26375259). The CC gastrointestinal tract develops normally (PubMed:18693275, CC PubMed:26375003, PubMed:26375259). They are however resistant to LPS- CC induced lethal septic shock (PubMed:26375259). Primary bone marrow- CC derived macrophages fail to undergo pyroptosis in response to canonical CC (acting via CASP1), as well as to non-canonical (acting via CASP4) CC inflammasome activators (PubMed:18693275, PubMed:26375003, CC PubMed:26375259). CASP1-mediated IL1B release is also impaired, but not CC CASP1 autoprocessing, nor IL1B maturation (PubMed:18693275, CC PubMed:26375003, PubMed:26375259). Reduced ability to protect against CC acute S.Typhimurium infection in the gut (PubMed:37988464). Increased CC resistance of the blood-brain barrier following infection, due to CC decreased non-canonical inflammasome activation and pyroptosis of CC endothelial cells (PubMed:38632402). {ECO:0000269|PubMed:18693275, CC ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:26375259, CC ECO:0000269|PubMed:37988464, ECO:0000269|PubMed:38632402}. 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 AlphaFoldDB; Q9D8T2; -. DR SMR; Q9D8T2; -. DR BioGRID; 213254; 2. DR DIP; DIP-61777N; -. DR IntAct; Q9D8T2; 2. DR STRING; 10090.ENSMUSP00000023238; -. DR ChEMBL; CHEMBL4523446; -. DR DrugCentral; Q9D8T2; -. DR GlyGen; Q9D8T2; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9D8T2; -. DR PhosphoSitePlus; Q9D8T2; -. DR SwissPalm; Q9D8T2; -. DR PaxDb; 10090-ENSMUSP00000023238; -. DR PeptideAtlas; Q9D8T2; -. DR ProteomicsDB; 269843; -. DR ABCD; Q9D8T2; 1 sequenced antibody. DR Antibodypedia; 27909; 194 antibodies from 31 providers. DR DNASU; 69146; -. DR Ensembl; ENSMUST00000023238.6; ENSMUSP00000023238.5; ENSMUSG00000022575.6. DR GeneID; 69146; -. DR KEGG; mmu:69146; -. DR UCSC; uc007whh.1; mouse. DR AGR; MGI:1916396; -. DR CTD; 79792; -. DR MGI; MGI:1916396; Gsdmd. DR VEuPathDB; HostDB:ENSMUSG00000022575; -. DR eggNOG; ENOG502S0IQ; Eukaryota. DR GeneTree; ENSGT00950000183140; -. DR HOGENOM; CLU_040752_1_0_1; -. DR InParanoid; Q9D8T2; -. DR OMA; STPWQEQ; -. DR OrthoDB; 5101111at2759; -. DR PhylomeDB; Q9D8T2; -. DR TreeFam; TF331886; -. DR Reactome; R-MMU-111457; Release of apoptotic factors from the mitochondria. DR Reactome; R-MMU-448706; Interleukin-1 processing. DR Reactome; R-MMU-5620971; Pyroptosis. DR Reactome; R-MMU-5686938; Regulation of TLR by endogenous ligand. DR Reactome; R-MMU-6798695; Neutrophil degranulation. DR BioGRID-ORCS; 69146; 2 hits in 77 CRISPR screens. DR PRO; PR:Q9D8T2; -. DR Proteomes; UP000000589; Chromosome 15. DR RNAct; Q9D8T2; Protein. DR Bgee; ENSMUSG00000022575; Expressed in small intestine Peyer's patch and 144 other cell types or tissues. DR ExpressionAtlas; Q9D8T2; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB. DR GO; GO:0072559; C:NLRP3 inflammasome complex; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl. 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:0022829; F:wide pore channel activity; IDA:UniProtKB. 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:0050729; P:positive regulation of inflammatory response; IDA:UniProt. 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:0009306; P:protein secretion; IDA:UniProt. DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB. DR InterPro; IPR040460; Gasdermin_pore. DR InterPro; IPR041263; Gasdermin_PUB. DR PANTHER; PTHR16399; GASDERMIN; 1. DR PANTHER; PTHR16399:SF15; GASDERMIN-D; 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 Glycoprotein; Immunity; Inflammasome; Inflammatory response; KW Innate immunity; Lipid-binding; Lipoprotein; Membrane; Mitochondrion; KW Necrosis; Nucleus; Palmitate; Phosphoprotein; Reference proteome; Secreted; KW Transcription; Transcription regulation; Transmembrane; KW Transmembrane beta strand. FT CHAIN 1..487 FT /note="Gasdermin-D" FT /id="PRO_0000148176" FT CHAIN 1..310 FT /note="Gasdermin-D, p40" FT /evidence="ECO:0000305|PubMed:35794369" FT /id="PRO_0000459020" FT CHAIN 1..276 FT /note="Gasdermin-D, N-terminal" FT /evidence="ECO:0000305|PubMed:27383986, FT ECO:0000305|PubMed:30135078, ECO:0000305|PubMed:32553275" FT /id="PRO_0000437528" FT CHAIN 1..88 FT /note="Gasdermin-D, p13" FT /evidence="ECO:0000305|PubMed:37327784" FT /id="PRO_0000459019" FT CHAIN 277..487 FT /note="Gasdermin-D, C-terminal" FT /evidence="ECO:0000305|PubMed:27383986, FT ECO:0000305|PubMed:30135078, ECO:0000305|PubMed:32553275" FT /id="PRO_0000437529" FT TRANSMEM 92..98 FT /note="Beta stranded" FT /evidence="ECO:0000250|UniProtKB:P57764" FT TRANSMEM 104..109 FT /note="Beta stranded" FT /evidence="ECO:0000250|UniProtKB:P57764" FT TRANSMEM 181..187 FT /note="Beta stranded" FT /evidence="ECO:0000250|UniProtKB:P57764" FT TRANSMEM 192..198 FT /note="Beta stranded" FT /evidence="ECO:0000250|UniProtKB:P57764" FT REGION 278..298 FT /note="Linker helix loop" FT /evidence="ECO:0000250|UniProtKB:P57764" FT SITE 88..89 FT /note="Cleavage; by CASP3 or CASP7" FT /evidence="ECO:0000269|PubMed:37327784" 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 ECO:0000269|PubMed:38538834, ECO:0000305|PubMed:30135078" FT SITE 310..311 FT /note="Cleavage; by papain" FT /evidence="ECO:0000269|PubMed:35794369" 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 LIPID 192 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:38530158, FT ECO:0000269|PubMed:38538834, ECO:0000269|PubMed:38599239" FT MUTAGEN 7..14 FT /note="KVVKNVIK->AVVANVIA: Reduced ability to induct FT pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 17..20 FT /note="SGSR->DGS: Renders Gsdmd susceptible to FT ubiquitination by S.flexneri IpaH7.8." FT /evidence="ECO:0000269|PubMed:36599845" 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 induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341" FT MUTAGEN 50..51 FT /note="FW->GG: Abolished ability to form a pore, leading to FT educed ability to induce pyroptosis." FT /evidence="ECO:0000269|PubMed:31097341, FT ECO:0000269|PubMed:33883744" 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 85..88 FT /note="DVVD->AAAA: Abolished cleavage by CASP3 and CASP7." FT /evidence="ECO:0000269|PubMed:37327784" 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. Abolished palmitoylation and ability to form a FT pore and mediate pyroptosis." FT /evidence="ECO:0000269|PubMed:27383986, FT ECO:0000269|PubMed:32820063, ECO:0000269|PubMed:38530158, FT ECO:0000269|PubMed:38538834" 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 Loss of CASP4/CASP11-induced cleavage. Abolished ability to FT induce pyroptosis following inactivation of MAP3K7/TAK1 by FT Yersinia toxin YopJ." FT /evidence="ECO:0000269|PubMed:26375259, FT ECO:0000269|PubMed:26611636, ECO:0000269|PubMed:30135078, FT ECO:0000269|PubMed:30361383, ECO:0000269|PubMed:32553275, FT ECO:0000269|PubMed:38538834" 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 309..313 FT /note="ELRQQ->AAAAA: Abolished generation of the Gasdermin- FT D, p40 chain and ability to promote secretion of IL33." FT /evidence="ECO:0000269|PubMed:35794369" FT MUTAGEN 309..313 FT /note="Missing: Abolished generation of the Gasdermin-D, FT p40 chain and ability to promote secretion of IL33." FT /evidence="ECO:0000269|PubMed:35794369" 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:0007829|PDB:6N9N" FT STRAND 19..21 FT /evidence="ECO:0007829|PDB:6N9N" FT HELIX 32..35 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 40..43 FT /evidence="ECO:0007829|PDB:6N9N" FT TURN 63..65 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 66..68 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 87..89 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 119..125 FT /evidence="ECO:0007829|PDB:6N9N" FT HELIX 128..137 FT /evidence="ECO:0007829|PDB:6N9N" FT HELIX 148..152 FT /evidence="ECO:0007829|PDB:6N9N" FT TURN 153..155 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 157..167 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 171..173 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 207..209 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 214..223 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 225..227 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 229..233 FT /evidence="ECO:0007829|PDB:6N9N" FT STRAND 274..277 FT /evidence="ECO:0007829|PDB:6VIE" FT STRAND 280..285 FT /evidence="ECO:0007829|PDB:6KMV" FT HELIX 289..304 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 308..321 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 325..341 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 350..356 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 357..359 FT /evidence="ECO:0007829|PDB:6AO3" FT STRAND 364..366 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 368..383 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 386..396 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 400..414 FT /evidence="ECO:0007829|PDB:6AO3" FT STRAND 418..420 FT /evidence="ECO:0007829|PDB:6VIE" FT STRAND 422..424 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 428..431 FT /evidence="ECO:0007829|PDB:6AO3" FT STRAND 436..439 FT /evidence="ECO:0007829|PDB:6VIE" FT HELIX 440..446 FT /evidence="ECO:0007829|PDB:6AO3" FT TURN 447..449 FT /evidence="ECO:0007829|PDB:6AO3" FT STRAND 454..457 FT /evidence="ECO:0007829|PDB:6AO3" FT STRAND 459..461 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 463..465 FT /evidence="ECO:0007829|PDB:6AO3" FT HELIX 466..482 FT /evidence="ECO:0007829|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 //