ID   GSDME_MOUSE             Reviewed;         512 AA.
AC   Q9Z2D3;
DT   21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   24-JAN-2024, entry version 141.
DE   RecName: Full=Gasdermin-E {ECO:0000250|UniProtKB:O60443};
DE   AltName: Full=Non-syndromic hearing impairment protein 5 homolog {ECO:0000305};
DE   Contains:
DE     RecName: Full=Gasdermin-E, N-terminal {ECO:0000250|UniProtKB:O60443};
DE              Short=GSDME-NT {ECO:0000250|UniProtKB:O60443};
DE   Contains:
DE     RecName: Full=Gasdermin-E, C-terminal {ECO:0000250|UniProtKB:O60443};
DE              Short=GSDME-CT {ECO:0000250|UniProtKB:O60443};
GN   Name=Gsdme {ECO:0000250|UniProtKB:O60443}; Synonyms=Dfna5, Dfna5h;
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 [MRNA].
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 [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Testis;
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   [3]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain;
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   [4]
RP   TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
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   [5]
RP   FUNCTION.
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   [6]
RP   FUNCTION.
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   [7]
RP   FUNCTION, AND ACTIVITY REGULATION.
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).
CC   -!- FUNCTION: [Gasdermin-E]: Precursor of a pore-forming protein that
CC       converts non-inflammatory apoptosis to pyroptosis. 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.
CC       {ECO:0000269|PubMed:32188940, ECO:0000269|PubMed:33852854}.
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:32188940). 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:33852854). Binds to inner leaflet lipids, bisphosphorylated
CC       phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate
CC       (By similarity). Cleavage by CASP3 switches CASP3-mediated apoptosis
CC       induced by TNF or danger signals, such as chemotherapy drugs, to
CC       pyroptosis (PubMed:32188940). Mediates secondary necrosis downstream of
CC       the mitochondrial apoptotic pathway and CASP3 activation as well as in
CC       response to viral agents (PubMed:28045099). Exhibits bactericidal
CC       activity (By similarity). Cleavage by GZMB promotes tumor suppressor
CC       activity by triggering robust anti-tumor immunity (PubMed:32188940).
CC       Suppresses tumors by mediating granzyme-mediated pyroptosis in target
CC       cells of natural killer (NK) cells: cleavage by granzyme B (GZMB),
CC       delivered to target cells from NK-cells, triggers pyroptosis of tumor
CC       cells and tumor suppression (By similarity). May play a role in the
CC       p53/TP53-regulated cellular response to DNA damage (By similarity).
CC       {ECO:0000250|UniProtKB:O60443, ECO:0000269|PubMed:28045099,
CC       ECO:0000269|PubMed:32188940, ECO:0000269|PubMed:33852854}.
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 (By similarity). The intrinsic pyroptosis-inducing activity is
CC       carried by the released N-terminal moiety (Gasdermin-E, N-terminal)
CC       following cleavage by CASP3 or granzyme B (GZMB) (By similarity).
CC       Activated by NLRP1 in the absence of GSDMD expression: NLRP1 cleaves
CC       and activates CASP8, promoting downstream activation of CASP3 and
CC       subsequent activation of GSDME (PubMed:33852854).
CC       {ECO:0000250|UniProtKB:O60443, ECO:0000269|PubMed:33852854}.
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   -!- SUBCELLULAR LOCATION: [Gasdermin-E, N-terminal]: Cell membrane
CC       {ECO:0000250|UniProtKB:O60443}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:Q5Y4Y6}.
CC   -!- SUBCELLULAR LOCATION: [Gasdermin-E]: Cytoplasm, cytosol
CC       {ECO:0000250|UniProtKB:O60443}.
CC   -!- TISSUE SPECIFICITY: Expressed in spleen, kidney, large and small
CC       intestine, testicle, stomach and by CD4(+)CD(8+) T cells in thymus
CC       (PubMed:28459430). Expressed by macrophages (PubMed:28045099).
CC       {ECO:0000269|PubMed:28045099, ECO:0000269|PubMed:28459430}.
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:0000250|UniProtKB:O60443}.
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:0000250|UniProtKB:O60443}.
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. Succination
CC       modification is catalyzed by a non-enzymatic reaction caused by an
CC       accumulation of fumarate. {ECO:0000250|UniProtKB:O60443}.
CC   -!- DISRUPTION PHENOTYPE: Mutant mice develop normally, including the
CC       immune system. After injection of the chemotherapy drug cisplatin, they
CC       look more healthy and vigorous than wild type.
CC       {ECO:0000269|PubMed:28459430}.
CC   -!- SIMILARITY: Belongs to the gasdermin family. {ECO:0000305}.
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DR   EMBL; AF073309; AAC69325.1; -; mRNA.
DR   EMBL; AK016561; BAB30305.1; -; mRNA.
DR   CCDS; CCDS20130.1; -.
DR   RefSeq; NP_061239.1; NM_018769.3.
DR   AlphaFoldDB; Q9Z2D3; -.
DR   STRING; 10090.ENSMUSP00000031845; -.
DR   iPTMnet; Q9Z2D3; -.
DR   PhosphoSitePlus; Q9Z2D3; -.
DR   MaxQB; Q9Z2D3; -.
DR   PaxDb; 10090-ENSMUSP00000031845; -.
DR   ProteomicsDB; 271468; -.
DR   Antibodypedia; 1157; 268 antibodies from 30 providers.
DR   DNASU; 54722; -.
DR   Ensembl; ENSMUST00000031845.13; ENSMUSP00000031845.7; ENSMUSG00000029821.16.
DR   Ensembl; ENSMUST00000170142.8; ENSMUSP00000126759.2; ENSMUSG00000029821.16.
DR   GeneID; 54722; -.
DR   KEGG; mmu:54722; -.
DR   UCSC; uc009bwx.1; mouse.
DR   AGR; MGI:1889850; -.
DR   CTD; 1687; -.
DR   MGI; MGI:1889850; Gsdme.
DR   VEuPathDB; HostDB:ENSMUSG00000029821; -.
DR   eggNOG; ENOG502QRAB; Eukaryota.
DR   GeneTree; ENSGT00940000155880; -.
DR   InParanoid; Q9Z2D3; -.
DR   OMA; DEMTNDC; -.
DR   OrthoDB; 2905407at2759; -.
DR   PhylomeDB; Q9Z2D3; -.
DR   TreeFam; TF352821; -.
DR   Reactome; R-MMU-111457; Release of apoptotic factors from the mitochondria.
DR   Reactome; R-MMU-5620971; Pyroptosis.
DR   Reactome; R-MMU-5686938; Regulation of TLR by endogenous ligand.
DR   BioGRID-ORCS; 54722; 2 hits in 76 CRISPR screens.
DR   ChiTaRS; Gsdme; mouse.
DR   PRO; PR:Q9Z2D3; -.
DR   Proteomes; UP000000589; Chromosome 6.
DR   RNAct; Q9Z2D3; Protein.
DR   Bgee; ENSMUSG00000029821; Expressed in pineal body and 257 other cell types or tissues.
DR   ExpressionAtlas; Q9Z2D3; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR   GO; GO:0005829; C:cytosol; ISO:MGI.
DR   GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR   GO; GO:1901612; F:cardiolipin binding; IDA:UniProtKB.
DR   GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; ISS:UniProtKB.
DR   GO; GO:0022829; F:wide pore channel activity; ISO:MGI.
DR   GO; GO:0071356; P:cellular response to tumor necrosis factor; ISS:UniProtKB.
DR   GO; GO:0098586; P:cellular response to virus; IMP:UniProtKB.
DR   GO; GO:0140507; P:granzyme-mediated programmed cell death signaling pathway; ISO:MGI.
DR   GO; GO:0042491; P:inner ear auditory receptor cell differentiation; IMP:MGI.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:MGI.
DR   GO; GO:0002839; P:positive regulation of immune response to tumor cell; ISO:MGI.
DR   GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR   GO; GO:0043410; P:positive regulation of MAPK cascade; ISS:UniProtKB.
DR   GO; GO:0012501; P:programmed cell death; ISS:UniProtKB.
DR   GO; GO:0070269; P:pyroptosis; IMP:UniProtKB.
DR   GO; GO:0007605; P:sensory perception of sound; ISO:MGI.
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; Q9Z2D3; MM.
PE   1: Evidence at protein level;
KW   Cell membrane; Cytoplasm; Membrane; Necrosis; Reference proteome;
KW   Transmembrane; Transmembrane beta strand.
FT   CHAIN           1..512
FT                   /note="Gasdermin-E"
FT                   /id="PRO_0000148179"
FT   CHAIN           1..270
FT                   /note="Gasdermin-E, N-terminal"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT                   /id="PRO_0000442749"
FT   CHAIN           271..499
FT                   /note="Gasdermin-E, C-terminal"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT                   /id="PRO_0000442750"
FT   REGION          1..56
FT                   /note="Membrane targeting domain"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT   SITE            270..271
FT                   /note="Cleavage; by CASP3 or granzyme B"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT   MOD_RES         45
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT   MOD_RES         156
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT   MOD_RES         168
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT   MOD_RES         180
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT   MOD_RES         235
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT   MOD_RES         411
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
FT   MOD_RES         420
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:O60443"
SQ   SEQUENCE   512 AA;  56631 MW;  13AFB8627773C4A5 CRC64;
     MFAKATRNFL KEVDAGGDLI SVSHLNDSDK LQLLSLVTKK KRYWCWQRPK YQILSATLED
     VLTEGHCLSP VVVESDFVKY ESKCENHKSG AIGTVVGKVK LNVGGKGVVE SHSSFGTLRK
     QEVDVQQLIQ DAVKRTVNMD NLVLQQVLES RNEVLCVLTQ KIMTTQKCVI SEHVQSEETC
     GGMVGIQTKT IQVSATEDGT VTTDTNVVLE IPAATTIAYG IMELFVKQDG QFEFCLLQGK
     HGGFEHERKL DSVYLDPLAY REFAFLDMLD GGQGISSQDG PLRVVKQATL HLERSFHPFA
     VLPAQQQRAL FCVLQKILFD EELLRALEQV CDDVAGGLWS SQAVLAMEEL TDSQQQDLTA
     FLQLVGYRIQ GEHPGPQDEV SNQKLFATAY FLVSALAEMP DNATVFLGTC CKLHVISSLC
     CLLHALSDDS VCDFHNPTLA PLRDTERFGI VQRLFASADI ALERMQFSAK ATILKDSCIF
     PLILHITLSG LSTLSKEHEE ELCQSGHATG QD
//