HERC5_HUMAN
ID HERC5_HUMAN Reviewed; 1024 AA.
AC Q9UII4; B2RTQ1; Q69G20;
DT 10-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=E3 ISG15--protein ligase HERC5;
DE EC=2.3.2.-;
DE AltName: Full=Cyclin-E-binding protein 1;
DE AltName: Full=HECT domain and RCC1-like domain-containing protein 5;
GN Name=HERC5; Synonyms=CEB1, CEBP1;
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], TISSUE SPECIFICITY, AND INTERACTION WITH CCNA1;
RP CCNB1; CCND1 AND CCNE1.
RC TISSUE=Embryonic kidney;
RX PubMed=10581175; DOI=10.1006/bbrc.1999.1777;
RA Mitsui K., Nakanishi M., Ohtsuka S., Norwood T.H., Okabayashi K.,
RA Miyamoto C., Tanaka K., Yoshimura A., Ohtsubo M.;
RT "A novel human gene encoding HECT domain and RCC1-like repeats interacts
RT with cyclins and is potentially regulated by the tumor suppressor
RT proteins.";
RL Biochem. Biophys. Res. Commun. 266:115-122(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF CYS-994, TISSUE SPECIFICITY, AND
RP INDUCTION.
RX PubMed=15331633; DOI=10.1242/jcs.01338;
RA Kroismayr R., Baranyi U., Stehlik C., Dorfleutner A., Binder B.R., Lipp J.;
RT "HERC5, a HECT E3 ubiquitin ligase tightly regulated in LPS activated
RT endothelial cells.";
RL J. Cell Sci. 117:4749-4756(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [5]
RP FUNCTION.
RX PubMed=16884686; DOI=10.1016/j.bbrc.2006.07.076;
RA Takeuchi T., Inoue S., Yokosawa H.;
RT "Identification and Herc5-mediated ISGylation of novel target proteins.";
RL Biochem. Biophys. Res. Commun. 348:473-477(2006).
RN [6]
RP FUNCTION, AND MUTAGENESIS OF CYS-994.
RX PubMed=16407192; DOI=10.1074/jbc.m512830200;
RA Dastur A., Beaudenon S., Kelley M., Krug R.M., Huibregtse J.M.;
RT "Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation
RT of ISG15 in human cells.";
RL J. Biol. Chem. 281:4334-4338(2006).
RN [7]
RP FUNCTION, MUTAGENESIS OF CYS-994, ISGYLATION, INDUCTION BY IFNB1, AND
RP INTERACTION WITH ISGYLATED HSPA8 AND TXNRD1.
RX PubMed=16815975; DOI=10.1073/pnas.0600397103;
RA Wong J.J., Pung Y.F., Sze N.S., Chin K.C.;
RT "HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I
RT IFN-induced ISGylation of protein targets.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:10735-10740(2006).
RN [8]
RP FUNCTION, AND MUTAGENESIS OF CYS-994.
RX PubMed=20385878; DOI=10.4049/jimmunol.0903588;
RA Tang Y., Zhong G., Zhu L., Liu X., Shan Y., Feng H., Bu Z., Chen H.,
RA Wang C.;
RT "Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1
RT protein.";
RL J. Immunol. 184:5777-5790(2010).
RN [9]
RP FUNCTION, MUTAGENESIS OF CYS-994, AND INTERACTION WITH IRF3.
RX PubMed=20308324; DOI=10.1128/mcb.01466-09;
RA Shi H.X., Yang K., Liu X., Liu X.Y., Wei B., Shan Y.F., Zhu L.H., Wang C.;
RT "Positive regulation of interferon regulatory factor 3 activation by Herc5
RT via ISG15 modification.";
RL Mol. Cell. Biol. 30:2424-2436(2010).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH 60S SUBUNIT, AND
RP MUTAGENESIS OF CYS-994.
RX PubMed=20542004; DOI=10.1016/j.molcel.2010.05.002;
RA Durfee L.A., Lyon N., Seo K., Huibregtsesend J.M.;
RT "The ISG15 conjugation system broadly targets newly synthesized proteins:
RT implications for the antiviral function of ISG15.";
RL Mol. Cell 38:722-732(2010).
RN [11]
RP FUNCTION, AND INTERACTION WITH INFLUENZA A VIRUS NS1.
RX PubMed=20133869; DOI=10.1073/pnas.0909144107;
RA Zhao C., Hsiang T.Y., Kuo R.L., Krug R.M.;
RT "ISG15 conjugation system targets the viral NS1 protein in influenza A
RT virus-infected cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:2253-2258(2010).
CC -!- FUNCTION: Major E3 ligase for ISG15 conjugation. Acts as a positive
CC regulator of innate antiviral response in cells induced by interferon.
CC Functions as part of the ISGylation machinery that recognizes target
CC proteins in a broad and relatively non-specific manner. Catalyzes
CC ISGylation of IRF3 which results in sustained activation, it attenuates
CC IRF3-PIN1 interaction, which antagonizes IRF3 ubiquitination and
CC degradation, and boosts the antiviral response. Catalyzes ISGylation of
CC influenza A viral NS1 which attenuates virulence; ISGylated NS1 fails
CC to form homodimers and thus to interact with its RNA targets. Catalyzes
CC ISGylation of papillomavirus type 16 L1 protein which results in
CC dominant-negative effect on virus infectivity. Physically associated
CC with polyribosomes, broadly modifies newly synthesized proteins in a
CC cotranslational manner. In an interferon-stimulated cell, newly
CC translated viral proteins are primary targets of ISG15.
CC {ECO:0000269|PubMed:16407192, ECO:0000269|PubMed:16815975,
CC ECO:0000269|PubMed:16884686, ECO:0000269|PubMed:20133869,
CC ECO:0000269|PubMed:20308324, ECO:0000269|PubMed:20385878,
CC ECO:0000269|PubMed:20542004}.
CC -!- SUBUNIT: Binds to CCNA1, CCNB1, CCND1 and CCNE1. Interacts with UBE2L6.
CC Interacts with IRF3, this interaction is marginal in resting cells but
CC enhanced upon viral infection. Interacts with influenza A virus NS1.
CC {ECO:0000269|PubMed:10581175, ECO:0000269|PubMed:16815975,
CC ECO:0000269|PubMed:20133869, ECO:0000269|PubMed:20308324,
CC ECO:0000269|PubMed:20542004}.
CC -!- INTERACTION:
CC Q9UII4; P03495: NS; Xeno; NbExp=3; IntAct=EBI-2339540, EBI-2548993;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:20542004}. Note=Associated with the polyribosomes,
CC probably via the 60S subunit.
CC -!- TISSUE SPECIFICITY: Expressed in testis and to a lesser degree in
CC brain, ovary and placenta. Found in most tissues at low levels.
CC {ECO:0000269|PubMed:10581175, ECO:0000269|PubMed:15331633}.
CC -!- INDUCTION: By IFNB1/IFN-beta. In endothelial cells, by TNF,
CC IL1B/interleukin-1B and by bacterial lipopolysaccharides (LPS), hardly
CC induced in other cells of the vascular wall such as primary smooth
CC muscle cells and fibroblasts. By viral infection.
CC {ECO:0000269|PubMed:15331633, ECO:0000269|PubMed:16815975}.
CC -!- PTM: ISGylated. {ECO:0000305|PubMed:16815975}.
CC -!- CAUTION: Was thought to be a ubiquitin ligase ubiquitinated by UBE2D1,
CC but was confirmed by numerous studies that it's main function is as E3
CC ISG15 ligase. {ECO:0000305|PubMed:15331633}.
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DR EMBL; AB027289; BAA88519.1; -; mRNA.
DR EMBL; AY337518; AAR00320.1; -; mRNA.
DR EMBL; AC083829; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC140716; AAI40717.1; -; mRNA.
DR CCDS; CCDS3630.1; -.
DR RefSeq; NP_057407.2; NM_016323.3.
DR AlphaFoldDB; Q9UII4; -.
DR SMR; Q9UII4; -.
DR BioGRID; 119365; 167.
DR DIP; DIP-44200N; -.
DR IntAct; Q9UII4; 43.
DR MINT; Q9UII4; -.
DR STRING; 9606.ENSP00000264350; -.
DR iPTMnet; Q9UII4; -.
DR PhosphoSitePlus; Q9UII4; -.
DR SwissPalm; Q9UII4; -.
DR BioMuta; HERC5; -.
DR DMDM; 296434523; -.
DR EPD; Q9UII4; -.
DR jPOST; Q9UII4; -.
DR MassIVE; Q9UII4; -.
DR MaxQB; Q9UII4; -.
DR PaxDb; Q9UII4; -.
DR PeptideAtlas; Q9UII4; -.
DR PRIDE; Q9UII4; -.
DR ProteomicsDB; 84527; -.
DR Antibodypedia; 25627; 99 antibodies from 23 providers.
DR DNASU; 51191; -.
DR Ensembl; ENST00000264350.8; ENSP00000264350.3; ENSG00000138646.9.
DR GeneID; 51191; -.
DR KEGG; hsa:51191; -.
DR MANE-Select; ENST00000264350.8; ENSP00000264350.3; NM_016323.4; NP_057407.2.
DR UCSC; uc003hrt.5; human.
DR CTD; 51191; -.
DR DisGeNET; 51191; -.
DR GeneCards; HERC5; -.
DR HGNC; HGNC:24368; HERC5.
DR HPA; ENSG00000138646; Tissue enhanced (testis).
DR MIM; 608242; gene.
DR neXtProt; NX_Q9UII4; -.
DR OpenTargets; ENSG00000138646; -.
DR PharmGKB; PA134973940; -.
DR VEuPathDB; HostDB:ENSG00000138646; -.
DR eggNOG; KOG0941; Eukaryota.
DR GeneTree; ENSGT00940000162703; -.
DR HOGENOM; CLU_002173_5_3_1; -.
DR InParanoid; Q9UII4; -.
DR OMA; WKMTVDT; -.
DR OrthoDB; 1062377at2759; -.
DR PhylomeDB; Q9UII4; -.
DR TreeFam; TF315189; -.
DR PathwayCommons; Q9UII4; -.
DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
DR Reactome; R-HSA-168928; DDX58/IFIH1-mediated induction of interferon-alpha/beta.
DR Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; Q9UII4; -.
DR BioGRID-ORCS; 51191; 10 hits in 1120 CRISPR screens.
DR GeneWiki; HERC5; -.
DR GenomeRNAi; 51191; -.
DR Pharos; Q9UII4; Tbio.
DR PRO; PR:Q9UII4; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q9UII4; protein.
DR Bgee; ENSG00000138646; Expressed in right testis and 159 other tissues.
DR ExpressionAtlas; Q9UII4; baseline and differential.
DR Genevisible; Q9UII4; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0030332; F:cyclin binding; IPI:MGI.
DR GO; GO:0042296; F:ISG15 transferase activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; TAS:Reactome.
DR GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0032020; P:ISG15-protein conjugation; IDA:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IDA:MGI.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; TAS:ProtInc.
DR GO; GO:0050688; P:regulation of defense response to virus; IDA:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR CDD; cd00078; HECTc; 1.
DR Gene3D; 2.130.10.30; -; 1.
DR InterPro; IPR000569; HECT_dom.
DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR InterPro; IPR009091; RCC1/BLIP-II.
DR InterPro; IPR000408; Reg_chr_condens.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00415; RCC1; 4.
DR PRINTS; PR00633; RCCNDNSATION.
DR SMART; SM00119; HECTc; 1.
DR SUPFAM; SSF50985; SSF50985; 1.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS00626; RCC1_2; 2.
DR PROSITE; PS50012; RCC1_3; 4.
PE 1: Evidence at protein level;
KW Antiviral defense; Cytoplasm; Immunity; Innate immunity;
KW Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1..1024
FT /note="E3 ISG15--protein ligase HERC5"
FT /id="PRO_0000206641"
FT REPEAT 96..155
FT /note="RCC1 1"
FT REPEAT 156..208
FT /note="RCC1 2"
FT REPEAT 209..260
FT /note="RCC1 3"
FT REPEAT 262..312
FT /note="RCC1 4"
FT REPEAT 314..364
FT /note="RCC1 5"
FT DOMAIN 702..1024
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT REGION 1..28
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 994
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT VARIANT 301
FT /note="A -> T (in dbSNP:rs17014143)"
FT /id="VAR_057123"
FT MUTAGEN 994
FT /note="C->A: Loss of activity; no effect on IRF3
FT interaction."
FT /evidence="ECO:0000269|PubMed:15331633,
FT ECO:0000269|PubMed:16407192, ECO:0000269|PubMed:16815975,
FT ECO:0000269|PubMed:20308324, ECO:0000269|PubMed:20385878,
FT ECO:0000269|PubMed:20542004"
FT CONFLICT 204
FT /note="M -> T (in Ref. 2; AAR00320)"
FT /evidence="ECO:0000305"
FT CONFLICT 419
FT /note="F -> S (in Ref. 2; AAR00320)"
FT /evidence="ECO:0000305"
FT CONFLICT 453
FT /note="K -> R (in Ref. 1; BAA88519)"
FT /evidence="ECO:0000305"
FT CONFLICT 498
FT /note="M -> V (in Ref. 1; BAA88519, 2; AAR00320 and 3;
FT AAI40717)"
FT /evidence="ECO:0000305"
FT CONFLICT 513
FT /note="A -> T (in Ref. 2; AAR00320)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1024 AA; 116852 MW; 1449C51A58269A6C CRC64;
MERRSRRKSR RNGRSTAGKA AATQPAKSPG AQLWLFPSAA GLHRALLRRV EVTRQLCCSP
GRLAVLERGG AGVQVHQLLA GSGGARTPKC IKLGKNMKIH SVDQGAEHML ILSSDGKPFE
YDNYSMKHLR FESILQEKKI IQITCGDYHS LALSKGGELF AWGQNLHGQL GVGRKFPSTT
TPQIVEHLAG VPLAQISAGE AHSMALSMSG NIYSWGKNEC GQLGLGHTES KDDPSLIEGL
DNQKVEFVAC GGSHSALLTQ DGLLFTFGAG KHGQLGHNST QNELRPCLVA ELVGYRVTQI
ACGRWHTLAY VSDLGKVFSF GSGKDGQLGN GGTRDQLMPL PVKVSSSEEL KLESHTSEKE
LIMIAGGNQS ILLWIKKENS YVNLKRTIPT LNEGTVKRWI ADVETKRWQS TKREIQEIFS
SPACLTGSFL RKRRTTEMMP VYLDLNKARN IFKELTQKDW ITNMITTCLK DNLLKRLPFH
SPPQEALEIF FLLPECPMMH ISNNWESLVV PFAKVVCKMS DQSSLVLEEY WATLQESTFS
KLVQMFKTAV ICQLDYWDES AEENGNVQAL LEMLKKLHRV NQVKCQLPES IFQVDELLHR
LNFFVEVCRR YLWKMTVDAS ENVQCCVIFS HFPFIFNNLS KIKLLHTDTL LKIESKKHKA
YLRSAAIEEE RESEFALRPT FDLTVRRNHL IEDVLNQLSQ FENEDLRKEL WVSFSGEIGY
DLGGVKKEFF YCLFAEMIQP EYGMFMYPEG ASCMWFPVKP KFEKKRYFFF GVLCGLSLFN
CNVANLPFPL ALFKKLLDQM PSLEDLKELS PDLGKNLQTL LDDEGDNFEE VFYIHFNVHW
DRNDTNLIPN GSSITVNQTN KRDYVSKYIN YIFNDSVKAV YEEFRRGFYK MCDEDIIKLF
HPEELKDVIV GNTDYDWKTF EKNARYEPGY NSSHPTIVMF WKAFHKLTLE EKKKFLVFLT
GTDRLQMKDL NNMKITFCCP ESWNERDPIR ALTCFSVLFL PKYSTMETVE EALQEAINNN
RGFG
