ID GSDME_HUMAN Reviewed; 496 AA. AC O60443; A4D156; B2RAX9; B3KT05; O14590; Q08AQ8; Q9UBV3; DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1999, sequence version 2. DT 27-MAR-2024, entry version 169. DE RecName: Full=Gasdermin-E {ECO:0000303|PubMed:28459430}; DE AltName: Full=Inversely correlated with estrogen receptor expression 1 {ECO:0000303|PubMed:9523727}; DE Short=ICERE-1 {ECO:0000303|PubMed:9523727}; DE AltName: Full=Non-syndromic hearing impairment protein 5 {ECO:0000303|PubMed:9771715}; DE Contains: DE RecName: Full=Gasdermin-E, N-terminal {ECO:0000303|PubMed:28459430}; DE Short=GSDME-NT {ECO:0000303|PubMed:28459430}; DE Contains: DE RecName: Full=Gasdermin-E, C-terminal {ECO:0000303|PubMed:28459430}; DE Short=GSDME-CT {ECO:0000303|PubMed:28459430}; GN Name=GSDME {ECO:0000303|PubMed:28459430, ECO:0000312|HGNC:HGNC:2810}; GN Synonyms=DFNA5 {ECO:0000303|PubMed:9771715}, ICERE1 GN {ECO:0000303|PubMed:9523727}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND INVOLVEMENT RP IN DFNA5. RC TISSUE=Cochlea; RX PubMed=9771715; DOI=10.1038/2503; RA Van Laer L., Huizing E.H., Verstreken M., van Zuijlen D., Wauters J.G., RA Bossuyt P.J., Van de Heyning P., McGuirt W.T., Smith R.J.H., Willems P.J., RA Legan P.K., Richardson G.P., Van Camp G.; RT "Nonsyndromic hearing impairment is associated with a mutation in DFNA5."; RL Nat. Genet. 20:194-197(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Van Laer L., Van Camp G.; RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RA Mei G., Yu W., Gibbs R.A.; RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Amygdala; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H., RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., RA Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT THR-142. RX PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D., RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., RA Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 5-496 (ISOFORM 1). RC TISSUE=Mammary gland; RX PubMed=9523727; DOI=10.1046/j.1432-1327.1998.2520169.x; RA Thompson D.A., Weigel R.J.; RT "Characterization of a gene that is inversely correlated with estrogen RT receptor expression (ICERE-1) in breast carcinomas."; RL Eur. J. Biochem. 252:169-177(1998). RN [10] RP SEQUENCE REVISION TO C-TERMINUS. RA Thompson D.A.; RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases. RN [11] RP FUNCTION IN TP53-MEDIATED CELLULAR RESPONSE. RX PubMed=16897187; DOI=10.1007/s10038-006-0004-6; RA Masuda Y., Futamura M., Kamino H., Nakamura Y., Kitamura N., Ohnishi S., RA Miyamoto Y., Ichikawa H., Ohta T., Ohki M., Kiyono T., Egami H., Baba H., RA Arakawa H.; RT "The potential role of DFNA5, a hearing impairment gene, in p53-mediated RT cellular response to DNA damage."; RL J. Hum. Genet. 51:652-664(2006). RN [12] RP INVOLVEMENT IN CRC. RX PubMed=18223688; DOI=10.1038/sj.onc.1211021; RA Kim M.S., Chang X., Yamashita K., Nagpal J.K., Baek J.H., Wu G., Trink B., RA Ratovitski E.A., Mori M., Sidransky D.; RT "Aberrant promoter methylation and tumor suppressive activity of the DFNA5 RT gene in colorectal carcinoma."; RL Oncogene 27:3624-3634(2008). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [15] RP FUNCTION. RX PubMed=21522185; DOI=10.1038/ejhg.2011.63; RA Op de Beeck K., Van Camp G., Thys S., Cools N., Callebaut I., Vrijens K., RA Van Nassauw L., Van Tendeloo V.F., Timmermans J.P., Van Laer L.; RT "The DFNA5 gene, responsible for hearing loss and involved in cancer, RT encodes a novel apoptosis-inducing protein."; RL Eur. J. Hum. Genet. 19:965-973(2011). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [17] RP INVOLVEMENT IN DFNA5. RX PubMed=19911014; DOI=10.1038/jhg.2009.114; RA Park H.J., Cho H.J., Baek J.I., Ben-Yosef T., Kwon T.J., Griffith A.J., RA Kim U.K.; RT "Evidence for a founder mutation causing DFNA5 hearing loss in East RT Asians."; RL J. Hum. Genet. 55:59-62(2010). RN [18] RP INVOLVEMENT IN DFNA5. RX PubMed=24506266; DOI=10.1111/ahg.12053; RA Nishio A., Noguchi Y., Sato T., Naruse T.K., Kimura A., Takagi A., RA Kitamura K.; RT "A DFNA5 mutation identified in Japanese families with autosomal dominant RT hereditary hearing loss."; RL Ann. Hum. Genet. 78:83-91(2014). RN [19] RP INVOLVEMENT IN DFNA5. RX PubMed=26236191; DOI=10.3389/fncel.2015.00231; RA Van Rossom S., Op de Beeck K., Hristovska V., Winderickx J., Van Camp G.; RT "The deafness gene DFNA5 induces programmed cell death through mitochondria RT and MAPK-related pathways."; RL Front. Cell. Neurosci. 9:231-231(2015). RN [20] RP FUNCTION, AND MUTAGENESIS OF ILE-313; PHE-388 AND ALA-392. RX PubMed=27281216; DOI=10.1038/nature18590; RA Ding J., Wang K., Liu W., She Y., Sun Q., Shi J., Sun H., Wang D.C., RA Shao F.; RT "Pore-forming activity and structural autoinhibition of the gasdermin RT family."; RL Nature 535:111-116(2016). RN [21] RP FUNCTION (GASDERMIN-E, N-TERMINAL), ACTIVITY REGULATION, CLEAVAGE BY CASP3, RP SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF ASP-267 AND ASP-270. RX PubMed=28459430; DOI=10.1038/nature22393; RA Wang Y., Gao W., Shi X., Ding J., Liu W., He H., Wang K., Shao F.; RT "Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a RT gasdermin."; RL Nature 547:99-103(2017). RN [22] RP FUNCTION (GASDERMIN-E, N-TERMINAL), ACTIVITY REGULATION, CLEAVAGE BY CASP3, RP SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF PHE-2; LYS-39; LYS-40; RP LYS-41 AND ASP-270. RX PubMed=28045099; DOI=10.1038/ncomms14128; RA Rogers C., Fernandes-Alnemri T., Mayes L., Alnemri D., Cingolani G., RA Alnemri E.S.; RT "Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to RT secondary necrotic/pyroptotic cell death."; RL Nat. Commun. 8:14128-14128(2017). RN [23] RP FUNCTION (GASDERMIN-E, N-TERMINAL), ACTIVITY REGULATION, CLEAVAGE BY GZMB, RP DOMAIN, MUTAGENESIS OF PHE-2 AND ASP-270, VARIANTS TYR-14; VAL-18; ASP-24; RP CYS-44; ILE-48; THR-137; GLU-199; LEU-212 AND ASN-217, AND CHARACTERIZATION RP OF VARIANTS TYR-14; VAL-18; ASP-24; CYS-44; ILE-48; THR-137; GLU-199; RP LEU-212 AND ASN-217. RX PubMed=32188940; DOI=10.1038/s41586-020-2071-9; RA Zhang Z., Zhang Y., Xia S., Kong Q., Li S., Liu X., Junqueira C., RA Meza-Sosa K.F., Mok T.M.Y., Ansara J., Sengupta S., Yao Y., Wu H., RA Lieberman J.; RT "Gasdermin E suppresses tumour growth by activating anti-tumour immunity."; RL Nature 579:415-420(2020). RN [24] RP SUCCINATION AT CYS-45; CYS-156; CYS-168; CYS-180; CYS-235; CYS-371; RP CYS-417; CYS-408 AND CYS-489. 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 [25] RP FUNCTION (GASDERMIN-E, N-TERMINAL), ACTIVITY REGULATION, AND CLEAVAGE BY RP GZMB. RX PubMed=31953257; DOI=10.1126/sciimmunol.aax7969; RA Liu Y., Fang Y., Chen X., Wang Z., Liang X., Zhang T., Liu M., Zhou N., RA Lv J., Tang K., Xie J., Gao Y., Cheng F., Zhou Y., Zhang Z., Hu Y., RA Zhang X., Gao Q., Zhang Y., Huang B.; RT "Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers RT cytokine release syndrome."; RL Sci. Immunol. 5:0-0(2020). RN [26] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF ASP-270. RX PubMed=33852854; DOI=10.1016/j.celrep.2021.108998; RA Zhou B., Abbott D.W.; RT "Gasdermin E permits interleukin-1 beta release in distinct sublytic and RT pyroptotic phases."; RL Cell Rep. 35:108998-108998(2021). RN [27] RP FUNCTION (MICROBIAL INFECTION). RX PubMed=35972780; DOI=10.7554/elife.73792; RA Zhao Z., Li Q., Ashraf U., Yang M., Zhu W., Gu J., Chen Z., Gu C., Si Y., RA Cao S., Ye J.; RT "Zika virus causes placental pyroptosis and associated adverse fetal RT outcomes by activating GSDME."; RL Elife 11:0-0(2022). RN [28] RP FUNCTION, ACTIVITY REGULATION, AND ACTIVITY REGULATION (MICROBIAL RP INFECTION). RX PubMed=35594856; DOI=10.1016/j.molcel.2022.04.033; RG COVID Human Genetic Effort; RA Planes R., Pinilla M., Santoni K., Hessel A., Passemar C., Lay K., RA Paillette P., Valadao A.C., Robinson K.S., Bastard P., Lam N., Fadrique R., RA Rossi I., Pericat D., Bagayoko S., Leon-Icaza S.A., Rombouts Y., RA Perouzel E., Tiraby M., Zhang Q., Cicuta P., Jouanguy E., Neyrolles O., RA Bryant C.E., Floto A.R., Goujon C., Lei F.Z., Martin-Blondel G., Silva S., RA Casanova J.L., Cougoule C., Reversade B., Marcoux J., Ravet E., Meunier E.; RT "Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung RT epithelial cells."; RL Mol. Cell 82:2385-2400(2022). CC -!- FUNCTION: [Gasdermin-E]: Precursor of a pore-forming protein that CC converts non-inflammatory apoptosis to pyroptosis (PubMed:27281216, CC PubMed:28459430, PubMed:33852854, PubMed:35594856). This form CC constitutes the precursor of the pore-forming protein: upon cleavage, CC the released N-terminal moiety (Gasdermin-E, N-terminal) binds to CC membranes and forms pores, triggering pyroptosis (PubMed:28459430). CC {ECO:0000269|PubMed:27281216, ECO:0000269|PubMed:28459430, CC ECO:0000269|PubMed:33852854, ECO:0000269|PubMed:35594856}. CC -!- FUNCTION: [Gasdermin-E, N-terminal]: Pore-forming protein produced by CC cleavage by CASP3 or granzyme B (GZMB), which converts non-inflammatory CC apoptosis to pyroptosis or promotes granzyme-mediated pyroptosis, CC respectively (PubMed:27281216, PubMed:28459430, PubMed:32188940, CC PubMed:33852854, PubMed:35594856). After cleavage, moves to the plasma CC membrane, homooligomerizes within the membrane and forms pores of 10-15 CC nanometers (nm) of inner diameter, allowing the release of mature CC interleukins (IL1B and IL16) and triggering pyroptosis CC (PubMed:28459430, PubMed:32188940, PubMed:33852854, PubMed:35594856). CC Binds to inner leaflet lipids, bisphosphorylated phosphatidylinositols, CC such as phosphatidylinositol (4,5)-bisphosphate (PubMed:28459430). CC Cleavage by CASP3 switches CASP3-mediated apoptosis induced by TNF or CC danger signals, such as chemotherapy drugs, to pyroptosis CC (PubMed:27281216, PubMed:28459430, PubMed:32188940). Mediates secondary CC necrosis downstream of the mitochondrial apoptotic pathway and CASP3 CC activation as well as in response to viral agents (PubMed:28045099). CC Exhibits bactericidal activity (PubMed:27281216). Cleavage by GZMB CC promotes tumor suppressor activity by triggering robust anti-tumor CC immunity (PubMed:21522185, PubMed:32188940). Suppresses tumors by CC mediating granzyme-mediated pyroptosis in target cells of natural CC killer (NK) cells: cleavage by granzyme B (GZMB), delivered to target CC cells from NK-cells, triggers pyroptosis of tumor cells and tumor CC suppression (PubMed:32188940, PubMed:31953257). May play a role in the CC p53/TP53-regulated cellular response to DNA damage (PubMed:16897187). CC {ECO:0000269|PubMed:16897187, ECO:0000269|PubMed:21522185, CC ECO:0000269|PubMed:27281216, ECO:0000269|PubMed:28045099, CC ECO:0000269|PubMed:28459430, ECO:0000269|PubMed:31953257, CC ECO:0000269|PubMed:32188940, ECO:0000269|PubMed:33852854, CC ECO:0000269|PubMed:35594856}. CC -!- FUNCTION: [Gasdermin-E, N-terminal]: (Microbial infection) Pore-forming CC protein, which promotes maternal placental pyroptosis in response to CC Zika virus infection, contributing to adverse fetal outcomes. CC {ECO:0000269|PubMed:35972780}. CC -!- ACTIVITY REGULATION: [Gasdermin-E]: 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:28045099, PubMed:28459430). The intrinsic pyroptosis- CC inducing activity is carried by the released N-terminal moiety CC (Gasdermin-E, N-terminal) following cleavage by CASP3 or granzyme B CC (GZMB) (PubMed:28459430, PubMed:32188940, PubMed:31953257, CC PubMed:35594856). Activated by NLRP1 in the absence of GSDMD CC expression: NLRP1 cleaves and activates CASP8, promoting downstream CC activation of CASP3 and subsequent activation of GSDME CC (PubMed:33852854, PubMed:35594856). {ECO:0000269|PubMed:28045099, CC ECO:0000269|PubMed:28459430, ECO:0000269|PubMed:31953257, CC ECO:0000269|PubMed:32188940, ECO:0000269|PubMed:33852854, CC ECO:0000269|PubMed:35594856}. CC -!- ACTIVITY REGULATION: (Microbial infection) Activated upon human CC coronavirus SARS-CoV-2 infection, leading to lung epithelial cell death CC (PubMed:35594856). Activation takes place in response to (1) activation CC of NLRP1 and (2) inactivation of GSDMD following NLRP1 and GSDMD CC cleavage by the SARS-CoV-2 3C-like proteinase nsp5 (PubMed:35594856). CC {ECO:0000269|PubMed:35594856}. CC -!- SUBUNIT: [Gasdermin-E, N-terminal]: Homooligomer; homooligomeric ring- CC shaped pore complex containing 27-28 subunits when inserted in the CC membrane. {ECO:0000250|UniProtKB:Q5Y4Y6}. CC -!- INTERACTION: CC O60443; Q96CG3: TIFA; NbExp=3; IntAct=EBI-719315, EBI-740711; CC -!- SUBCELLULAR LOCATION: [Gasdermin-E, N-terminal]: Cell membrane CC {ECO:0000269|PubMed:28045099, ECO:0000269|PubMed:28459430}; Multi-pass CC membrane protein {ECO:0000250|UniProtKB:Q5Y4Y6}. CC -!- SUBCELLULAR LOCATION: [Gasdermin-E]: Cytoplasm, cytosol CC {ECO:0000269|PubMed:28045099}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Long; CC IsoId=O60443-1; Sequence=Displayed; CC Name=2; Synonyms=Short; CC IsoId=O60443-2; Sequence=VSP_004190; CC Name=3; CC IsoId=O60443-3; Sequence=VSP_044276; CC -!- TISSUE SPECIFICITY: Expressed in cochlea (PubMed:9771715). Low level of CC expression in heart, brain, placenta, lung, liver, skeletal muscle, CC kidney and pancreas, with highest expression in placenta CC (PubMed:9771715). {ECO:0000269|PubMed:9771715}. CC -!- DOMAIN: Intramolecular interactions between N- and C-terminal domains CC may be important for autoinhibition in the absence of activation CC signal. The intrinsic pyroptosis-inducing activity is carried by the N- CC terminal domain, that is released upon cleavage by CASP3 or granzyme B CC (GZMB). {ECO:0000269|PubMed:28045099, ECO:0000269|PubMed:28459430, CC ECO:0000269|PubMed:32188940}. CC -!- PTM: Cleavage at Asp-270 by CASP3 (mature and uncleaved precursor CC forms) or granzyme B (GZMB) relieves autoinhibition and is sufficient CC to initiate pyroptosis. {ECO:0000269|PubMed:28045099, CC ECO:0000269|PubMed:28459430, ECO:0000269|PubMed:31953257, CC ECO:0000269|PubMed:32188940}. CC -!- PTM: [Gasdermin-E]: Succination by the Krebs cycle intermediate CC fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits CC 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 -!- DISEASE: Deafness, autosomal dominant, 5 (DFNA5) [MIM:600994]: A form CC of non-syndromic sensorineural hearing loss. Sensorineural deafness CC results from damage to the neural receptors of the inner ear, the nerve CC pathways to the brain, or the area of the brain that receives sound CC information. {ECO:0000269|PubMed:19911014, ECO:0000269|PubMed:24506266, CC ECO:0000269|PubMed:26236191, ECO:0000269|PubMed:9771715}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Note=Is a tumor suppressor gene with an important role in CC colorectal cancer (CRC). {ECO:0000303|PubMed:18223688}. CC -!- SIMILARITY: Belongs to the gasdermin family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB83938.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC Sequence=AAC39635.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={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; AF073308; AAC69324.1; -; mRNA. DR EMBL; AF075171; AAC69326.1; -; mRNA. DR EMBL; AF131765; AAD20039.1; -; mRNA. DR EMBL; AK094714; BAG52917.1; -; mRNA. DR EMBL; AK314402; BAG37026.1; -; mRNA. DR EMBL; AC003093; AAB83938.1; ALT_SEQ; Genomic_DNA. DR EMBL; CH236948; EAL24246.1; -; Genomic_DNA. DR EMBL; CH471073; EAW93813.1; -; Genomic_DNA. DR EMBL; BC125065; AAI25066.1; -; mRNA. DR EMBL; AF007790; AAC39635.2; ALT_INIT; mRNA. DR CCDS; CCDS47563.1; -. [O60443-3] DR CCDS; CCDS5389.1; -. [O60443-1] DR RefSeq; NP_001120925.1; NM_001127453.1. [O60443-1] DR RefSeq; NP_001120926.1; NM_001127454.1. [O60443-3] DR RefSeq; NP_004394.1; NM_004403.2. [O60443-1] DR RefSeq; XP_016867291.1; XM_017011802.1. [O60443-3] DR AlphaFoldDB; O60443; -. DR BioGRID; 108049; 62. DR IntAct; O60443; 19. DR MINT; O60443; -. DR STRING; 9606.ENSP00000339587; -. DR TCDB; 1.C.123.1.5; the pore-forming gasdermin (gasdermin) family. DR GlyGen; O60443; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O60443; -. DR PhosphoSitePlus; O60443; -. DR BioMuta; GSDME; -. DR EPD; O60443; -. DR jPOST; O60443; -. DR MassIVE; O60443; -. DR MaxQB; O60443; -. DR PaxDb; 9606-ENSP00000339587; -. DR PeptideAtlas; O60443; -. DR ProteomicsDB; 3659; -. DR ProteomicsDB; 49403; -. [O60443-1] DR ProteomicsDB; 49404; -. [O60443-2] DR Antibodypedia; 1157; 268 antibodies from 30 providers. DR DNASU; 1687; -. DR Ensembl; ENST00000342947.9; ENSP00000339587.3; ENSG00000105928.16. [O60443-1] DR Ensembl; ENST00000409970.6; ENSP00000387119.1; ENSG00000105928.16. [O60443-3] DR Ensembl; ENST00000419307.6; ENSP00000401332.1; ENSG00000105928.16. [O60443-3] DR Ensembl; ENST00000645220.1; ENSP00000494186.1; ENSG00000105928.16. [O60443-1] DR GeneID; 1687; -. DR KEGG; hsa:1687; -. DR MANE-Select; ENST00000645220.1; ENSP00000494186.1; NM_001127453.2; NP_001120925.1. DR UCSC; uc003sxa.2; human. [O60443-1] DR AGR; HGNC:2810; -. DR CTD; 1687; -. DR DisGeNET; 1687; -. DR GeneCards; GSDME; -. DR GeneReviews; GSDME; -. DR HGNC; HGNC:2810; GSDME. DR HPA; ENSG00000105928; Low tissue specificity. DR MalaCards; GSDME; -. DR MIM; 600994; phenotype. DR MIM; 608798; gene. DR neXtProt; NX_O60443; -. DR OpenTargets; ENSG00000105928; -. DR Orphanet; 90635; Rare autosomal dominant non-syndromic sensorineural deafness type DFNA. DR PharmGKB; PA27281; -. DR VEuPathDB; HostDB:ENSG00000105928; -. DR eggNOG; ENOG502QRAB; Eukaryota. DR GeneTree; ENSGT00940000155880; -. DR HOGENOM; CLU_042999_0_0_1; -. DR InParanoid; O60443; -. DR OMA; DEMTNDC; -. DR OrthoDB; 2905407at2759; -. DR PhylomeDB; O60443; -. DR TreeFam; TF352821; -. DR PathwayCommons; O60443; -. DR Reactome; R-HSA-111457; Release of apoptotic factors from the mitochondria. DR Reactome; R-HSA-5620971; Pyroptosis. DR Reactome; R-HSA-5686938; Regulation of TLR by endogenous ligand. DR Reactome; R-HSA-9710421; Defective pyroptosis. DR SignaLink; O60443; -. DR BioGRID-ORCS; 1687; 9 hits in 1147 CRISPR screens. DR ChiTaRS; DFNA5; human. DR GeneWiki; DFNA5; -. DR GenomeRNAi; 1687; -. DR Pharos; O60443; Tbio. DR PRO; PR:O60443; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; O60443; Protein. DR Bgee; ENSG00000105928; Expressed in germinal epithelium of ovary and 190 other cell types or tissues. DR ExpressionAtlas; O60443; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:1901612; F:cardiolipin binding; IDA:UniProtKB. DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:UniProtKB. DR GO; GO:0022829; F:wide pore channel activity; IDA:UniProt. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB. DR GO; GO:0098586; P:cellular response to virus; IDA:UniProtKB. DR GO; GO:0042491; P:inner ear auditory receptor cell differentiation; IEA:Ensembl. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB. DR GO; GO:0002839; P:positive regulation of immune response to tumor cell; IDA:UniProt. DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IDA:UniProtKB. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:UniProtKB. DR GO; GO:0012501; P:programmed cell death; IMP:UniProtKB. DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB. DR GO; GO:0007605; P:sensory perception of sound; TAS:ProtInc. DR InterPro; IPR040460; Gasdermin_pore. DR InterPro; IPR041263; Gasdermin_PUB. DR InterPro; IPR042377; GSDME. DR PANTHER; PTHR15207:SF1; GASDERMIN-E; 1. DR PANTHER; PTHR15207; NONSYNDROMIC HEARING IMPAIRMENT PROTEIN; 1. DR Pfam; PF04598; Gasdermin; 1. DR Pfam; PF17708; Gasdermin_C; 1. DR Genevisible; O60443; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Cytoplasm; Deafness; Membrane; KW Necrosis; Non-syndromic deafness; Reference proteome; Transmembrane; KW Transmembrane beta strand; Tumor suppressor. FT CHAIN 1..496 FT /note="Gasdermin-E" FT /id="PRO_0000148178" FT CHAIN 1..270 FT /note="Gasdermin-E, N-terminal" FT /evidence="ECO:0000269|PubMed:27281216, FT ECO:0000305|PubMed:28459430, ECO:0000305|PubMed:32188940" FT /id="PRO_0000442786" FT CHAIN 271..496 FT /note="Gasdermin-E, C-terminal" FT /evidence="ECO:0000305|PubMed:28459430" FT /id="PRO_0000442787" FT REGION 1..56 FT /note="Membrane targeting domain" FT /evidence="ECO:0000269|PubMed:28045099" FT SITE 270..271 FT /note="Cleavage; by CASP3 or granzyme B" FT /evidence="ECO:0000269|PubMed:28459430, FT ECO:0000269|PubMed:32188940" FT MOD_RES 45 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 156 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 168 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 180 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 235 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 371 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 408 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 417 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT MOD_RES 489 FT /note="S-(2-succinyl)cysteine" FT /evidence="ECO:0000269|PubMed:32820063" FT VAR_SEQ 1..395 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.2, ECO:0000303|Ref.3" FT /id="VSP_004190" FT VAR_SEQ 1..164 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044276" FT VARIANT 14 FT /note="D -> Y (in a breast carcinoma sample; somatic FT mutation; reduced ability to induce pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083903" FT VARIANT 18 FT /note="D -> V (in a colon adenocarcinoma sample; somatic FT mutation; reduced ability to induce pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083904" FT VARIANT 24 FT /note="N -> D (in a colon adenocarcinoma sample; somatic FT mutation; reduced ability to induce pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083905" FT VARIANT 44 FT /note="W -> C (in a lung cancer adenocarcinoma sample; FT somatic mutation; reduced ability to induce pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083906" FT VARIANT 48 FT /note="R -> I (in an uterine corpus endometrioid carcinoma FT sample; somatic mutation; reduced ability to induce FT pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083907" FT VARIANT 137 FT /note="I -> T (in an uterine corpus endometrioid carcinoma FT sample; somatic mutation; reduced ability to induce FT pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083908" FT VARIANT 142 FT /note="P -> T (in dbSNP:rs754554)" FT /evidence="ECO:0000269|PubMed:12690205" FT /id="VAR_030824" FT VARIANT 174 FT /note="M -> T (in dbSNP:rs876306)" FT /id="VAR_053102" FT VARIANT 199 FT /note="G -> E (in an uterine corpus endometrioid carcinoma FT sample; somatic mutation; reduced ability to induce FT pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083909" FT VARIANT 207 FT /note="V -> M (in dbSNP:rs12540919)" FT /id="VAR_030825" FT VARIANT 212 FT /note="P -> L (in a melanoma sample; somatic mutation; FT reduced ability to induce pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083910" FT VARIANT 217 FT /note="I -> N (in a lung cancer adenocarcinoma sample; FT somatic mutation; reduced ability to induce pyroptosis)" FT /evidence="ECO:0000269|PubMed:32188940" FT /id="VAR_083911" FT MUTAGEN 2 FT /note="F->A: No effect on plasma membrane targeting. FT Decreases induction of necrotic activity. Disrupts plasma FT membrane targeting and induction of necrotic activity; when FT associated with A-40." FT /evidence="ECO:0000269|PubMed:28045099, FT ECO:0000269|PubMed:32188940" FT MUTAGEN 39 FT /note="K->A: Disrupts plasma membrane targeting and FT induction of necrotic activity; when associated with A-40 FT and/or A-41." FT /evidence="ECO:0000269|PubMed:28045099" FT MUTAGEN 40 FT /note="K->A: No effect on plasma membrane targeting. No FT effect on induction of cytotoxivity. Disrupts plasma FT membrane targeting and induction of necrotic activity; when FT associated with A-2 or A-39 and A-41." FT /evidence="ECO:0000269|PubMed:28045099" FT MUTAGEN 41 FT /note="K->A: Disrupts plasma membrane targeting and FT induction of necrotic activity; when associated with A-39 FT and/or A-41." FT /evidence="ECO:0000269|PubMed:28045099" FT MUTAGEN 267 FT /note="D->A: Abolishes cleavage by CASP3. Abolishes FT pyroptosis induction." FT /evidence="ECO:0000269|PubMed:28459430" FT MUTAGEN 270 FT /note="D->A,E: Abolishes cleavage by CASP3 or granzyme B. FT Abolishes pyroptosis induction." FT /evidence="ECO:0000269|PubMed:28045099, FT ECO:0000269|PubMed:28459430, ECO:0000269|PubMed:32188940, FT ECO:0000269|PubMed:33852854" FT MUTAGEN 313 FT /note="I->D: No spontaneous pyroptosis-inducing activity." FT /evidence="ECO:0000269|PubMed:27281216" FT MUTAGEN 388 FT /note="F->D: Low spontaneous pyroptosis-inducing activity." FT /evidence="ECO:0000269|PubMed:27281216" FT MUTAGEN 392 FT /note="A->D: Low spontaneous pyroptosis-inducing activity." FT /evidence="ECO:0000269|PubMed:27281216" SQ SEQUENCE 496 AA; 54555 MW; A407C9AC31AA716B CRC64; MFAKATRNFL REVDADGDLI AVSNLNDSDK LQLLSLVTKK KRFWCWQRPK YQFLSLTLGD VLIEDQFPSP VVVESDFVKY EGKFANHVSG TLETALGKVK LNLGGSSRVE SQSSFGTLRK QEVDLQQLIR DSAERTINLR NPVLQQVLEG RNEVLCVLTQ KITTMQKCVI SEHMQVEEKC GGIVGIQTKT VQVSATEDGN VTKDSNVVLE IPAATTIAYG VIELYVKLDG QFEFCLLRGK QGGFENKKRI DSVYLDPLVF REFAFIDMPD AAHGISSQDG PLSVLKQATL LLERNFHPFA ELPEPQQTAL SDIFQAVLFD DELLMVLEPV CDDLVSGLSP TVAVLGELKP RQQQDLVAFL QLVGCSLQGG CPGPEDAGSK QLFMTAYFLV SALAEMPDSA AALLGTCCKL QIIPTLCHLL RALSDDGVSD LEDPTLTPLK DTERFGIVQR LFASADISLE RLKSSVKAVI LKDSKVFPLL LCITLNGLCA LGREHS //