CASP8_DROME
ID CASP8_DROME Reviewed; 494 AA.
AC Q8IRY7; O02433; O76797; O76798; Q95T94; Q9UB42; Q9W5E3;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
DT 16-JUN-2009, sequence version 3.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Caspase-8;
DE EC=3.4.22.61;
DE AltName: Full=Death-related ced-3/NEDD2-like protein;
DE Contains:
DE RecName: Full=Caspase-8 subunit p15;
DE Contains:
DE RecName: Full=Caspase-8 subunit p10;
DE Flags: Precursor;
GN Name=Dredd; Synonyms=DCP2; ORFNames=CG7486;
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS D; E AND ALPHA), FUNCTION, SUBUNIT,
RP PROTEOLYTIC CLEAVAGE, SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RC TISSUE=Embryo {ECO:0000269|PubMed:9740659};
RX PubMed=9740659; DOI=10.1006/dbio.1998.9000;
RA Chen P., Rodriguez A., Erskine R., Thach T., Abrams J.M.;
RT "Dredd, a novel effector of the apoptosis activators reaper, grim, and hid
RT in Drosophila.";
RL Dev. Biol. 201:202-216(1998).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley {ECO:0000269|PubMed:10731132};
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [3] {ECO:0000305}
RP GENOME REANNOTATION, AND ALTERNATIVE SPLICING.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [4] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Oregon-R {ECO:0000269|PubMed:10731137};
RX PubMed=10731137; DOI=10.1126/science.287.5461.2220;
RA Benos P.V., Gatt M.K., Ashburner M., Murphy L., Harris D., Barrell B.G.,
RA Ferraz C., Vidal S., Brun C., Demailles J., Cadieu E., Dreano S., Gloux S.,
RA Lelaure V., Mottier S., Galibert F., Borkova D., Minana B., Kafatos F.C.,
RA Louis C., Siden-Kiamos I., Bolshakov S., Papagiannakis G., Spanos L.,
RA Cox S., Madueno E., de Pablos B., Modolell J., Peter A., Schoettler P.,
RA Werner M., Mourkioti F., Beinert N., Dowe G., Schaefer U., Jaeckle H.,
RA Bucheton A., Callister D.M., Campbell L.A., Darlamitsou A., Henderson N.S.,
RA McMillan P.J., Salles C., Tait E.A., Valenti P., Saunders R.D.C.,
RA Glover D.M.;
RT "From sequence to chromosome: the tip of the X chromosome of D.
RT melanogaster.";
RL Science 287:2220-2222(2000).
RN [5] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM F).
RC STRAIN=Berkeley {ECO:0000269|PubMed:12537569};
RC TISSUE=Head {ECO:0000269|PubMed:12537569};
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN [6] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] OF 25-494 (ISOFORM E).
RX PubMed=9380701; DOI=10.1073/pnas.94.20.10717;
RA Inohara N., Koseki T., Hu Y., Chen S., Nunez G.;
RT "CLARP, a death effector domain-containing protein interacts with caspase-8
RT and regulates apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:10717-10722(1997).
RN [7] {ECO:0000305}
RP FUNCTION, TISSUE SPECIFICITY, AND MUTAGENESIS OF GLY-98 AND TRP-436.
RX PubMed=11269502; DOI=10.1093/embo-reports/kvd073;
RA Leulier F., Rodriguez A., Khush R.S., Abrams J.M., Lemaitre B.;
RT "The Drosophila caspase Dredd is required to resist Gram-negative bacterial
RT infection.";
RL EMBO Rep. 1:353-358(2000).
RN [8]
RP FUNCTION, INTERACTION WITH FADD, AND SUBCELLULAR LOCATION.
RX PubMed=10934188; DOI=10.1074/jbc.c000341200;
RA Hu S., Yang X.;
RT "dFADD, a novel death domain-containing adapter protein for the Drosophila
RT caspase DREDD.";
RL J. Biol. Chem. 275:30761-30764(2000).
RN [9]
RP FUNCTION, UBIQUITINATION, MUTAGENESIS OF GLY-98, AND INTERACTION WITH FADD
RP AND DIAP2.
RX PubMed=22549468; DOI=10.1038/emboj.2012.121;
RA Meinander A., Runchel C., Tenev T., Chen L., Kim C.H., Ribeiro P.S.,
RA Broemer M., Leulier F., Zvelebil M., Silverman N., Meier P.;
RT "Ubiquitylation of the initiator caspase DREDD is required for innate
RT immune signalling.";
RL EMBO J. 31:2770-2783(2012).
CC -!- FUNCTION: Effector of the programmed cell death (PCD) activators rpr,
CC grim and hid (PubMed:9740659). May play an apoptotic role in the
CC germline as well as soma. Fadd interacts with Dredd to promote cleavage
CC of Dredd and is necessary and sufficient for enhancing Dredd-induced
CC apoptosis (PubMed:10934188). Plays a role in the innate immune
CC response. Required for resistance to Gram-negative bacterial infection
CC (PubMed:11269502). Diap2-mediated ubiquitination of Dredd is critical
CC for processing of imd and rel and the subsequent expression of
CC antimicrobial genes such as DptA (PubMed:22549468).
CC {ECO:0000269|PubMed:10934188, ECO:0000269|PubMed:11269502,
CC ECO:0000269|PubMed:22549468, ECO:0000269|PubMed:9740659}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Strict requirement for Asp at position P1 and has a preferred
CC cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).;
CC EC=3.4.22.61;
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged
CC heterodimers, each one formed by a 15 kDa (caspase-8 subunit p15) and a
CC 10 kDa (caspase-8 subunit p10) subunit (PubMed:9740659). Interacts (via
CC N-terminus) with Diap2; likely to bind Diap2 simultaneously with Fadd
CC to form a trimeric complex (PubMed:10934188, PubMed:22549468).
CC {ECO:0000269|PubMed:10934188, ECO:0000269|PubMed:22549468,
CC ECO:0000269|PubMed:9740659}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10934188,
CC ECO:0000269|PubMed:9740659}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=E; Synonyms=Caspase-8 delta;
CC IsoId=Q8IRY7-1; Sequence=Displayed;
CC Name=D; Synonyms=Caspase-8 gamma;
CC IsoId=Q8IRY7-2; Sequence=VSP_050749;
CC Name=F;
CC IsoId=Q8IRY7-3; Sequence=VSP_050750, VSP_050751;
CC Name=alpha {ECO:0000269|PubMed:9740659};
CC IsoId=Q8IRY7-4; Sequence=VSP_050748;
CC -!- TISSUE SPECIFICITY: Constitutively expressed in fat bodies of larvae
CC and adults. {ECO:0000269|PubMed:11269502}.
CC -!- DEVELOPMENTAL STAGE: Expressed both maternally and zygotically. Embryos
CC exhibit ubiquitous low level of expression until stage 11 and then
CC expression becomes spatially and temporally restricted to areas of PCD.
CC {ECO:0000269|PubMed:9740659}.
CC -!- PTM: Polyubiquitinated by Diap2 following activation of the immune
CC deficiency (Imd) pathway. {ECO:0000269|PubMed:22549468}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAL25314.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF007016; AAC31214.1; -; mRNA.
DR EMBL; AF083894; AAC33117.1; -; mRNA.
DR EMBL; AF083895; AAC33118.1; -; mRNA.
DR EMBL; AE014298; AAF45533.3; -; Genomic_DNA.
DR EMBL; AE014298; AAN09022.2; -; Genomic_DNA.
DR EMBL; AE014298; AAN09023.2; -; Genomic_DNA.
DR EMBL; AL031581; CAA20893.1; -; Genomic_DNA.
DR EMBL; AY060275; AAL25314.1; ALT_INIT; mRNA.
DR EMBL; AF031652; AAC15843.1; -; mRNA.
DR PIR; T13385; T13385.
DR RefSeq; NP_477249.3; NM_057901.4. [Q8IRY7-1]
DR RefSeq; NP_477250.3; NM_057902.4. [Q8IRY7-3]
DR RefSeq; NP_477251.3; NM_057903.4. [Q8IRY7-2]
DR AlphaFoldDB; Q8IRY7; -.
DR SMR; Q8IRY7; -.
DR BioGRID; 57579; 74.
DR IntAct; Q8IRY7; 5.
DR MINT; Q8IRY7; -.
DR STRING; 7227.FBpp0113052; -.
DR MEROPS; C14.040; -.
DR PaxDb; Q8IRY7; -.
DR DNASU; 31011; -.
DR EnsemblMetazoa; FBtr0114559; FBpp0113051; FBgn0020381. [Q8IRY7-2]
DR EnsemblMetazoa; FBtr0114560; FBpp0113052; FBgn0020381. [Q8IRY7-1]
DR EnsemblMetazoa; FBtr0114561; FBpp0113053; FBgn0020381. [Q8IRY7-3]
DR GeneID; 31011; -.
DR KEGG; dme:Dmel_CG7486; -.
DR CTD; 31011; -.
DR FlyBase; FBgn0020381; Dredd.
DR VEuPathDB; VectorBase:FBgn0020381; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00940000160994; -.
DR InParanoid; Q8IRY7; -.
DR PhylomeDB; Q8IRY7; -.
DR Reactome; R-DME-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-DME-214397; Assembly of the PGN:PGRP-LC/LE receptor 'signalling complex'.
DR Reactome; R-DME-214399; Activated IkappaB kinase (IKK) complex, Phospho IRD5:KEY dimer, phosphorylates REL in the PGN:PGRP-LC/LE receptor 'signalling complex'.
DR Reactome; R-DME-214411; REL binds to DREDD in the PGN:PGRP-LC/LE receptor 'signalling complex'.
DR Reactome; R-DME-214416; Phosphorylated REL is cleaved by and dissociates from DREDD.
DR Reactome; R-DME-448706; Interleukin-1 processing.
DR SignaLink; Q8IRY7; -.
DR BioGRID-ORCS; 31011; 0 hits in 3 CRISPR screens.
DR ChiTaRS; gem; fly.
DR GenomeRNAi; 31011; -.
DR PRO; PR:Q8IRY7; -.
DR Proteomes; UP000000803; Chromosome X.
DR Bgee; FBgn0020381; Expressed in saliva-secreting gland and 18 other tissues.
DR ExpressionAtlas; Q8IRY7; baseline and differential.
DR Genevisible; Q8IRY7; DM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0008656; F:cysteine-type endopeptidase activator activity involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; TAS:FlyBase.
DR GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; IBA:GO_Central.
DR GO; GO:0004175; F:endopeptidase activity; IDA:FlyBase.
DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR GO; GO:0006952; P:defense response; IMP:FlyBase.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IMP:UniProtKB.
DR GO; GO:0006955; P:immune response; IMP:FlyBase.
DR GO; GO:0045087; P:innate immune response; TAS:FlyBase.
DR GO; GO:0043069; P:negative regulation of programmed cell death; IMP:FlyBase.
DR GO; GO:0061057; P:peptidoglycan recognition protein signaling pathway; IDA:FlyBase.
DR GO; GO:0048935; P:peripheral nervous system neuron development; IMP:FlyBase.
DR GO; GO:0006963; P:positive regulation of antibacterial peptide biosynthetic process; TAS:FlyBase.
DR GO; GO:0006964; P:positive regulation of biosynthetic process of antibacterial peptides active against Gram-negative bacteria; IMP:UniProtKB.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IMP:FlyBase.
DR GO; GO:0045089; P:positive regulation of innate immune response; HMP:FlyBase.
DR GO; GO:0016485; P:protein processing; IDA:FlyBase.
DR GO; GO:0007291; P:sperm individualization; IMP:FlyBase.
DR CDD; cd00032; CASc; 1.
DR InterPro; IPR029030; Caspase-like_dom_sf.
DR InterPro; IPR002398; Pept_C14.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR001309; Pept_C14_p20.
DR InterPro; IPR015917; Pept_C14A.
DR PANTHER; PTHR10454; PTHR10454; 1.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00115; CASc; 1.
DR SUPFAM; SSF52129; SSF52129; 1.
DR PROSITE; PS01122; CASPASE_CYS; 1.
DR PROSITE; PS50207; CASPASE_P10; 1.
DR PROSITE; PS50208; CASPASE_P20; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Cytoplasm; Hydrolase; Immunity;
KW Innate immunity; Protease; Reference proteome; Thiol protease;
KW Ubl conjugation; Zymogen.
FT PROPEP 1..242
FT /evidence="ECO:0000250"
FT /id="PRO_0000004636"
FT CHAIN 243..400
FT /note="Caspase-8 subunit p15"
FT /id="PRO_0000004637"
FT PROPEP 401..410
FT /evidence="ECO:0000250"
FT /id="PRO_0000004638"
FT CHAIN 411..494
FT /note="Caspase-8 subunit p10"
FT /id="PRO_0000004639"
FT ACT_SITE 345
FT /evidence="ECO:0000250"
FT ACT_SITE 386
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..128
FT /note="Missing (in isoform alpha)"
FT /evidence="ECO:0000303|PubMed:9740659"
FT /id="VSP_050748"
FT VAR_SEQ 273..278
FT /note="Missing (in isoform D)"
FT /evidence="ECO:0000303|PubMed:9740659"
FT /id="VSP_050749"
FT VAR_SEQ 279..284
FT /note="KFLSPD -> VSSLQY (in isoform F)"
FT /evidence="ECO:0000303|PubMed:12537569"
FT /id="VSP_050750"
FT VAR_SEQ 285..494
FT /note="Missing (in isoform F)"
FT /evidence="ECO:0000303|PubMed:12537569"
FT /id="VSP_050751"
FT MUTAGEN 98
FT /note="G->R: In D44; reduces polyubiquitination by Diap2,
FT abolishes rel cleavage and blocks expression of DptA
FT following bacterial infection. No effect on binding to
FT Diap2 or Fadd, processing, dimerization, catalytic activity
FT or stability."
FT /evidence="ECO:0000269|PubMed:11269502,
FT ECO:0000269|PubMed:22549468"
FT MUTAGEN 436
FT /note="W->R: In L23; blocks expression of DptA following
FT bacterial infection."
FT /evidence="ECO:0000269|PubMed:11269502"
FT CONFLICT 481
FT /note="K -> N (in Ref. 1; AAC33117/AAC33118)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 494 AA; 56153 MW; B9730DB3FDC58D4C CRC64;
MAGSNLLIHL DTIDQNDLIY VERDMNFAQK VGLCFLLYGD DHSDATYILQ KLLAMTRSDF
PQSDLLIKFA KSRPETWRRH LVEALCIIGA RKVLRRLGFC WQELRMHYLP HIAGITLHVH
PLLKSLYRMC EELSLVQSGR LLLDVREKVE SQQAGDPLRF YDPAYLEIFL LDWLTRRSIK
LGDINAAGSD VQLLVGHLKS NGLQAQANLL KDTIISNAPE PDAAGTAAMA VKQEIESDNQ
QSYCSTQIDA LKLTRENAGI ALIINQQKFH RNVSRDNMKF LSPDPLRRRD GTDVDKERLI
EVFSSMGYNV EAYDNVDHMG IIERIRSACD RSLVRDSLVV FILSHGFEEA VYASNSIAMK
ITDIEDLLCS YDTLYYKPKL LIIQACQEKL VHKKKPNELF RIDVTTVSPD QHIDMLRAMS
TVNGYAALRH TQTGSWFIGS LCDAIDRRSA SEHIADILTI VTNEVSKKRG SNDESMVPNV
KSTFRQHVYF PPRL
