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 08-JUN-2016, entry version 92. DE RecName: Full=Gasdermin-D; DE AltName: Full=Gasdermin domain-containing protein 1; GN Name=Gsdmdc1; Synonyms=Gsdmd; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi; OC Muroidea; Muridae; 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., RA Davis M.J., Wilming L.G., Aidinis V., Allen J.E., RA Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., RA Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., RA Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., RA Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., RA di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., RA Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., RA Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., RA Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., RA Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., RA Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., RA Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., RA Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., RA Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., RA Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., RA Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., RA Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., RA Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., RA 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., RA Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., RA Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., RA Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., RA Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., RA Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., RA Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., RA Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., RA Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., RA Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., RA Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., RA Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., RA 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 RT project: 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., RA Zhong C.Q., Han J.; RT "Gasdermin D is an executor of pyroptosis and required for RT interleukin-1beta secretion."; RL Cell Res. 25:1285-1298(2015). RN [4] RP PROTEIN SEQUENCE OF 277-288, FUNCTION, DISRUPTION PHENOTYPE, RP MUTAGENESIS OF 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., RA Warming S., Cuellar T., Haley B., Roose-Girma M., Phung Q.T., RA Liu P.S., Lill J.R., Li H., Wu J., Kummerfeld S., Zhang J., Lee W.P., RA Snipas S.J., Salvesen G.S., Morris L.X., Fitzgerald L., Zhang Y., RA Bertram E.M., 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 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 RT expression."; RL Cell 143:1174-1189(2010). RN [6] 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 [7] RP FUNCTION, DISRUPTION PHENOTYPE, AND AUTOINHIBITION. RX PubMed=26375003; DOI=10.1038/nature15514; RA Shi J., Zhao Y., Wang K., Shi X., Wang Y., Huang H., Zhuang Y., RA Cai T., Wang F., Shao F.; RT "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell RT death."; RL Nature 526:660-665(2015). CC -!- FUNCTION: Component of inflammasomes responsible for the execution CC of pyroptosis and the release of mature IL1B. In response to CC canonical, as well as non-canonical (such as cytosolic LPS) CC inflammasome activators, undergoes cleavage by inflammatory CC caspases CASP1 and CASP4, respectively. The released N-terminal CC moiety promotes pyroptosis and release of mature IL1B. CC {ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:26375259, CC ECO:0000269|PubMed:26611636}. CC -!- SUBUNIT: In response to a canonical inflammasome stimulus, such as CC nigericin, recruited to NLRP3 inflammasone with similar kinetics CC to that of proCASP1. Although this recruitment is also observed in CC the absence of PYCARD, it is more efficient in its presence. CC {ECO:0000269|PubMed:26611636}. CC -!- SUBCELLULAR LOCATION: Inflammasome {ECO:0000269|PubMed:26611636}. CC Note=In response to a canonical inflammasome stimulus, such as CC nigericin, recruited to NLRP3 inflammasone with similar kinetics CC to that of proCASP1. {ECO:0000269|PubMed:26611636}. CC -!- DEVELOPMENTAL STAGE: Expression starts at 8.5 dpc and increases CC from 13.5 dpc on. Still detected after birth. CC {ECO:0000269|PubMed:18693275}. CC -!- DOMAIN: Intramolecular interactions between N- and C-terminal CC domains may be important for autoinhibition in the absence of CC cleavage by inflammatory caspases CASP1 or CASP4. The intrinsic CC pyroptosis-inducing activity is carried by the N-terminal domain CC that is released upon cleavage by inflammatory caspases. CC {ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:26375259, CC ECO:0000269|PubMed:26611636}. CC -!- PTM: Cleavage at Asp-276 by CASP1 (mature and uncleaved precursor CC forms) or CASP4 relieves autoinhibition and is sufficient to CC initiate pyroptosis. {ECO:0000269|PubMed:26375259, CC ECO:0000269|PubMed:26611636}. CC -!- DISRUPTION PHENOTYPE: Knockout mice are born at the expected CC Mendelian rate and do not exhibit any overt phenotype in normal CC housing conditions. The gastrointestinal tract develops normally. CC They are however resistant to LPS-induced lethal septic shock. CC Primary bone marrow-derived macrophages fail to undergo pyroptosis CC in response to canonical (acting via CASP1), as well as to non- CC canonical (acting via CASP4) inflammasome activators. CASP1- CC mediated IL1B release is also impaired, but not CASP1 CC autoprocessing, nor IL1B maturation. {ECO:0000269|PubMed:18693275, CC ECO:0000269|PubMed:26375003, 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 UniGene; Mm.27385; -. DR ProteinModelPortal; Q9D8T2; -. DR DIP; DIP-61777N; -. DR STRING; 10090.ENSMUSP00000023238; -. DR iPTMnet; Q9D8T2; -. DR PhosphoSite; Q9D8T2; -. DR EPD; Q9D8T2; -. DR MaxQB; Q9D8T2; -. DR PaxDb; Q9D8T2; -. DR PRIDE; Q9D8T2; -. 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; ENOG410IKA4; Eukaryota. DR eggNOG; ENOG4111D9N; LUCA. DR GeneTree; ENSGT00530000063218; -. DR HOGENOM; HOG000082450; -. DR HOVERGEN; HBG099862; -. DR InParanoid; Q9D8T2; -. DR OMA; VIGSDWD; -. DR OrthoDB; EOG71K636; -. DR PhylomeDB; Q9D8T2; -. DR TreeFam; TF331886; -. DR PRO; PR:Q9D8T2; -. DR Proteomes; UP000000589; Chromosome 15. DR Bgee; Q9D8T2; -. DR CleanEx; MM_GSDMD; -. DR Genevisible; Q9D8T2; MM. DR GO; GO:0072559; C:NLRP3 inflammasome complex; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0031668; P:cellular response to extracellular stimulus; IDA:MGI. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW. DR GO; GO:0050718; P:positive regulation of interleukin-1 beta secretion; IDA:UniProtKB. DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB. DR InterPro; IPR007677; Gasdermin. DR PANTHER; PTHR16399; PTHR16399; 1. DR Pfam; PF04598; Gasdermin; 1. PE 1: Evidence at protein level; KW Complete proteome; Cytoplasm; Direct protein sequencing; Immunity; KW Inflammasome; Inflammatory response; Innate immunity; Necrosis; KW Phosphoprotein; Reference proteome. FT CHAIN 1 487 Gasdermin-D. FT /FTId=PRO_0000148176. FT REGION 1 244 Triggers pyroptosis. FT {ECO:0000250|UniProtKB:P57764}. FT SITE 276 277 Cleavage (by inflammatory caspases CASP1 FT and CASP4). FT {ECO:0000269|PubMed:26375259}. FT MOD_RES 38 38 Phosphotyrosine. FT {ECO:0000250|UniProtKB:P57764}. FT MUTAGEN 105 105 I->N: Loss of cytosolic LPS-induced IL1B FT release and pyroptosis in bone marrow- FT derived macrophages. No effect on protein FT expression. No effect on cleavage by FT CASP4. {ECO:0000269|PubMed:26375259}. FT MUTAGEN 276 276 D->A,N: Loss of CASP1-induced cleavage, FT pyroptosis and IL1B release. FT {ECO:0000269|PubMed:26375259, FT ECO:0000269|PubMed:26611636}. 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 //