GSDME_MOUSE
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 03-AUG-2022, entry version 133.
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).
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:0000250|UniProtKB:O60443}.
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, triggering pyroptosis (By
CC similarity). 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}.
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. The intrinsic pyroptosis-inducing activity is carried by the
CC released N-terminal moiety (Gasdermin-E, N-terminal) following cleavage
CC by CASP3 or granzyme B (GZMB). {ECO:0000250|UniProtKB:O60443}.
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; Q9Z2D3; -.
DR PRIDE; Q9Z2D3; -.
DR ProteomicsDB; 271468; -.
DR Antibodypedia; 1157; 232 antibodies from 30 providers.
DR DNASU; 54722; -.
DR Ensembl; ENSMUST00000031845; ENSMUSP00000031845; ENSMUSG00000029821.
DR Ensembl; ENSMUST00000170142; ENSMUSP00000126759; ENSMUSG00000029821.
DR GeneID; 54722; -.
DR KEGG; mmu:54722; -.
DR UCSC; uc009bwx.1; mouse.
DR CTD; 1687; -.
DR MGI; MGI:1889850; Gsdme.
DR VEuPathDB; HostDB:ENSMUSG00000029821; -.
DR eggNOG; ENOG502QRAB; Eukaryota.
DR GeneTree; ENSGT00940000155880; -.
DR InParanoid; Q9Z2D3; -.
DR OMA; CLIQQTK; -.
DR OrthoDB; 1397132at2759; -.
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 71 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 254 other tissues.
DR ExpressionAtlas; Q9Z2D3; baseline and differential.
DR Genevisible; Q9Z2D3; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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; ISS:UniProtKB.
DR GO; GO:0008219; P:cell death; ISS:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:0042491; P:inner ear auditory receptor cell differentiation; IMP:MGI.
DR GO; GO:0070265; P:necrotic cell death; IMP:UniProtKB.
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; ISS:UniProtKB.
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:0070269; P:pyroptosis; ISS: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; PTHR15207; 1.
DR Pfam; PF04598; Gasdermin; 1.
DR Pfam; PF17708; Gasdermin_C; 1.
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
