GSDME_HUMAN
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 03-AUG-2022, entry version 160.
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},
GN ICERE1 {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).
CC -!- FUNCTION: [Gasdermin-E]: Precursor of a pore-forming protein that
CC converts non-inflammatory apoptosis to pyroptosis (PubMed:27281216,
CC PubMed:28459430). This form constitutes the precursor of the pore-
CC forming protein: upon cleavage, the released N-terminal moiety
CC (Gasdermin-E, N-terminal) binds to membranes and forms pores,
CC triggering pyroptosis (PubMed:28459430). {ECO:0000269|PubMed:27281216,
CC ECO:0000269|PubMed:28459430}.
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). After
CC cleavage, moves to the plasma membrane, homooligomerizes within the
CC membrane and forms pores of 10-15 nanometers (nm) of inner diameter,
CC triggering pyroptosis (PubMed:28459430, PubMed:32188940). Binds to
CC inner leaflet lipids, bisphosphorylated phosphatidylinositols, such as
CC phosphatidylinositol (4,5)-bisphosphate (PubMed:28459430). Cleavage by
CC CASP3 switches CASP3-mediated apoptosis induced by TNF or danger
CC signals, such as chemotherapy drugs, to pyroptosis (PubMed:27281216,
CC PubMed:28459430, PubMed:32188940). Mediates secondary necrosis
CC downstream of the mitochondrial apoptotic pathway and CASP3 activation
CC as well as in response to viral agents (PubMed:28045099). Exhibits
CC bactericidal activity (PubMed:27281216). Cleavage by GZMB promotes
CC tumor suppressor activity by triggering robust anti-tumor immunity
CC (PubMed:21522185, PubMed:32188940). Suppresses tumors by mediating
CC granzyme-mediated pyroptosis in target cells of natural killer (NK)
CC cells: cleavage by granzyme B (GZMB), delivered to target cells from
CC NK-cells, triggers pyroptosis of tumor cells and tumor suppression
CC (PubMed:32188940, PubMed:31953257). May play a role in the p53/TP53-
CC 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}.
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 {ECO:0000269|PubMed:28045099, ECO:0000269|PubMed:28459430,
CC ECO:0000269|PubMed:31953257, ECO:0000269|PubMed:32188940}.
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};
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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; 47.
DR IntAct; O60443; 16.
DR MINT; O60443; -.
DR STRING; 9606.ENSP00000339587; -.
DR TCDB; 1.C.123.1.5; the pore-forming gasdermin (gasdermin) family.
DR iPTMnet; O60443; -.
DR PhosphoSitePlus; O60443; -.
DR BioMuta; GSDME; -.
DR EPD; O60443; -.
DR jPOST; O60443; -.
DR MassIVE; O60443; -.
DR MaxQB; O60443; -.
DR PaxDb; O60443; -.
DR PeptideAtlas; O60443; -.
DR PRIDE; O60443; -.
DR ProteomicsDB; 3659; -.
DR ProteomicsDB; 49403; -. [O60443-1]
DR ProteomicsDB; 49404; -. [O60443-2]
DR Antibodypedia; 1157; 232 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 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; 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; CLIQQTK; -.
DR OrthoDB; 1397132at2759; -.
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 1073 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 188 other tissues.
DR ExpressionAtlas; O60443; baseline and differential.
DR Genevisible; O60443; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:UniProtKB.
DR GO; GO:0008219; P:cell death; IMP:UniProtKB.
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:0140507; P:granzyme-mediated programmed cell death signaling pathway; IDA:UniProtKB.
DR GO; GO:0042491; P:inner ear auditory receptor cell differentiation; IEA:Ensembl.
DR GO; GO:0070265; P:necrotic cell death; IDA:UniProtKB.
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:UniProtKB.
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: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; PTHR15207; 1.
DR Pfam; PF04598; Gasdermin; 1.
DR Pfam; PF17708; Gasdermin_C; 1.
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 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
