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Protein

E3 ubiquitin-protein ligase ICP0

Gene

ICP0

Organism
Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Evades nuclear antiviral defenses triggered by dsDNA viruses. Acts during the initial stages of lytic infection and the reactivation of latent viral genome. Prevents the antiviral effect of nuclear bodies by degrading host PML and SP100. Prevents antiviral response to viral DNA induced by IFI16 by degrading it. Additionally, inhibits host IRF3 nuclear signaling to prevent interferon production by the infected cells. Interestingly, the E3 ubiquitin ligase activity associated with the RING finger domain does not seem to be directly required to inhibit the activation of IRF3 but instead plays a critical role in modulating the cellular localization of ICP0. Upon reactivation of latent genome, suppresses the silencing of viral DNA by dissociating either HDAC1 or HDAC2 from the HDAC-RCOR1-REST-KDM1A complex localized at the ND10 structures and causes their dispersal. Two cellular histone ubiquitin ligases RNF8 and RNF168 are also targeted by ICP0 for degradation, leading to a loss of ubiquitinated forms of H2A, a relief of transcriptional repression, and the activation of latent viral genomes. Enhances the localization of host CCND3 to ND10 bodies that serve as precursors of replication compartments to enable efficient viral replication. Like many RING-finger E3 ubiquitin ligases, ICP0 can induce its own ubiquitination, an activity that promotes its instability due to its targeting to the 26S proteasome for degradation. ICP0 restricts this process by recruiting the cellular ubiquitin-specific protease USP7 that cleaves the anchored ubiquitin chains from ICP0, thereby promoting its stabilization.7 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri116 – 15742RING-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  • DNA binding Source: UniProtKB-KW
  • ligase activity Source: UniProtKB-KW
  • ubiquitin-protein transferase activity Source: AgBase
  • zinc ion binding Source: InterPro

GO - Biological processi

  • disruption by symbiont of host cell PML body Source: UniProtKB
  • modulation by virus of host protein ubiquitination Source: UniProtKB-KW
  • positive regulation of protein catabolic process Source: AgBase
  • protein polyubiquitination Source: AgBase
  • release from viral latency Source: AgBase
  • response to type I interferon Source: BHF-UCL
  • suppression by virus of host exit from mitosis Source: UniProtKB-KW
  • suppression by virus of host IRF3 activity Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator, Ligase

Keywords - Biological processi

Host-virus interaction, Inhibition of host innate immune response by virus, Inhibition of host IRF3 by virus, Inhibition of host mitotic exit by virus, Inhibition of host RLR pathway by virus, Modulation of host cell cycle by virus, Modulation of host ubiquitin pathway by viral E3 ligase, Modulation of host ubiquitin pathway by virus, Transcription, Transcription regulation, Ubl conjugation pathway, Viral immunoevasion

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase ICP0 (EC:6.3.2.-)
Alternative name(s):
Alpha-0 protein
Immediate-early protein IE110
Trans-acting transcriptional protein ICP0
VMW110
Gene namesi
Name:ICP0
Synonyms:IE110
OrganismiHuman herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1)
Taxonomic identifieri10299 [NCBI]
Taxonomic lineageiVirusesdsDNA viruses, no RNA stageHerpesviralesHerpesviridaeAlphaherpesvirinaeSimplexvirus
Virus hostiHomo sapiens (Human) [TaxID: 9606]
ProteomesiUP000009294 Componenti: Genome

Subcellular locationi

GO - Cellular componenti

  • host cell cytoplasm Source: UniProtKB-SubCell
  • host cell nucleus Source: UniProtKB
  • viral tegument Source: CACAO
Complete GO annotation...

Keywords - Cellular componenti

Host cytoplasm, Host nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi67 – 671T → A: Abolishes interaction host RNF8. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 775775E3 ubiquitin-protein ligase ICP0PRO_0000056352Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei67 – 671Phosphothreonine; by host; by CK11 Publication

Post-translational modificationi

Phosphorylated at Thr-67, leading to promote interaction with host RNF8.1 Publication
Auto-ubiquitinated. Deubiquitinated by host USP7; leading to stabilize it.2 Publications

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Expressioni

Keywords - Developmental stagei

Early protein

Interactioni

Subunit structurei

Interacts directly with human RCOR1/CoREST protein, leading to the disruption of the human BHC corepressor complex. Interacts with human CENPA, leading to its degradation. Interacts with human USP7; this interaction modulates ICP0 stability. Interacts with human CDC34. Interacts (when phosphorylated) with human RNF8 (via FHA domain). Interacts with human TRIM27.7 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CCND3P302813EBI-6148881,EBI-375013From a different organism.
HDAC3O153793EBI-6148881,EBI-607682From a different organism.
HDAC4P565243EBI-6148881,EBI-308629From a different organism.
HDAC5Q9UQL63EBI-6148881,EBI-715576From a different organism.
HDAC7Q8WUI43EBI-6148881,EBI-1048378From a different organism.

Protein-protein interaction databases

BioGridi971426. 4 interactions.
971427. 25 interactions.
DIPiDIP-42446N.
IntActiP08393. 12 interactions.
MINTiMINT-1345075.

Structurei

3D structure databases

ProteinModelPortaliP08393.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi233 – 24311Poly-AspAdd
BLAST
Compositional biasi305 – 3084Poly-Gly
Compositional biasi558 – 56811Poly-SerAdd
BLAST

Sequence similaritiesi

Belongs to the simplexviruses ICp0 family.Curated
Contains 1 RING-type zinc finger.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri116 – 15742RING-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Family and domain databases

Gene3Di3.30.40.10. 1 hit.
InterProiIPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamiPF00097. zf-C3HC4. 1 hit.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
[Graphical view]
PROSITEiPS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P08393-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MEPRPGASTR RPEGRPQREP APDVWVFPCD RDLPDSSDSE AETEVGGRGD
60 70 80 90 100
ADHHDDDSAS EADSTDTELF ETGLLGPQGV DGGAVSGGSP PREEDPGSCG
110 120 130 140 150
GAPPREDGGS DEGDVCAVCT DEIAPHLRCD TFPCMHRFCI PCMKTWMQLR
160 170 180 190 200
NTCPLCNAKL VYLIVGVTPS GSFSTIPIVN DPQTRMEAEE AVRAGTAVDF
210 220 230 240 250
IWTGNQRFAP RYLTLGGHTV RALSPTHPEP TTDEDDDDLD DADYVPPAPR
260 270 280 290 300
RTPRAPPRRG AAAPPVTGGA SHAAPQPAAA RTAPPSAPIG PHGSSNTNTT
310 320 330 340 350
TNSSGGGGSR QSRAAAPRGA SGPSGGVGVG VGVVEAEAGR PRGRTGPLVN
360 370 380 390 400
RPAPLANNRD PIVISDSPPA SPHRPPAAPM PGSAPRPGPP ASAAASGPAR
410 420 430 440 450
PRAAVAPCVR APPPGPGPRA PAPGAEPAAR PADARRVPQS HSSLAQAANQ
460 470 480 490 500
EQSLCRARAT VARGSGGPGV EGGHGPSRGA APSGAAPLPS AASVEQEAAV
510 520 530 540 550
RPRKRRGSGQ ENPSPQSTRP PLAPAGAKRA ATHPPSDSGP GGRGQGGPGT
560 570 580 590 600
PLTSSAASAS SSSASSSSAP TPAGAASSAA GAASSSASAS SGGAVGALGG
610 620 630 640 650
RQEETSLGPR AASGPRGPRK CARKTRHAET SGAVPAGGLT RYLPISGVSS
660 670 680 690 700
VVALSPYVNK TITGDCLPIL DMETGNIGAY VVLVDQTGNM ATRLRAAVPG
710 720 730 740 750
WSRRTLLPET AGNHVMPPEY PTAPASEWNS LWMTPVGNML FDQGTLVGAL
760 770
DFRSLRSRHP WSGEQGASTR DEGKQ
Length:775
Mass (Da):78,457
Last modified:August 1, 1988 - v1
Checksum:iDF38A1C539DAB15C
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X14112 Genomic DNA. Translation: CAA32336.1.
X14112 Genomic DNA. Translation: CAA32293.1.
X04614 Genomic DNA. Translation: CAA28285.1.
PIRiA29152. EDBE11.
RefSeqiNP_044601.1. NC_001806.1.
NP_044660.1. NC_001806.1.

Genome annotation databases

GeneIDi2703389.
2703390.
KEGGivg:2703389.
vg:2703390.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X14112 Genomic DNA. Translation: CAA32336.1.
X14112 Genomic DNA. Translation: CAA32293.1.
X04614 Genomic DNA. Translation: CAA28285.1.
PIRiA29152. EDBE11.
RefSeqiNP_044601.1. NC_001806.1.
NP_044660.1. NC_001806.1.

3D structure databases

ProteinModelPortaliP08393.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi971426. 4 interactions.
971427. 25 interactions.
DIPiDIP-42446N.
IntActiP08393. 12 interactions.
MINTiMINT-1345075.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi2703389.
2703390.
KEGGivg:2703389.
vg:2703390.

Family and domain databases

Gene3Di3.30.40.10. 1 hit.
InterProiIPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamiPF00097. zf-C3HC4. 1 hit.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
[Graphical view]
PROSITEiPS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1."
    McGeoch D.J., Dalrymple M.A., Davison A.J., Dolan A., Frame M.C., McNab D., Perry L.J., Scott J.E., Taylor P.
    J. Gen. Virol. 69:1531-1574(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  2. "Characterization of the IE110 gene of herpes simplex virus type 1."
    Perry L.J., Rixon F.J., Everett R.D., Frame M.C., McGeoch D.J.
    J. Gen. Virol. 67:2365-2380(1986) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  3. "The DNA sequences of the long repeat region and adjoining parts of the long unique region in the genome of herpes simplex virus type 1."
    Perry L.J., McGeoch D.J.
    J. Gen. Virol. 69:2831-2846(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  4. "Degradation of nucleosome-associated centromeric histone H3-like protein CENP-A induced by herpes simplex virus type 1 protein ICP0."
    Lomonte P., Sullivan K.F., Everett R.D.
    J. Biol. Chem. 276:5829-5835(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HUMAN CENPA.
  5. "The infected cell protein 0 of herpes simplex virus 1 dynamically interacts with proteasomes, binds and activates the cdc34 E2 ubiquitin-conjugating enzyme, and possesses in vitro E3 ubiquitin ligase activity."
    Van Sant C., Hagglund R., Lopez P., Roizman B.
    Proc. Natl. Acad. Sci. U.S.A. 98:8815-8820(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HUMAN CDC34.
  6. "Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP."
    Holowaty M.N., Sheng Y., Nguyen T., Arrowsmith C., Frappier L.
    J. Biol. Chem. 278:47753-47761(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HUMAN USP7.
  7. "A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7."
    Canning M., Boutell C., Parkinson J., Everett R.D.
    J. Biol. Chem. 279:38160-38168(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: AUTOUBIQUITINATION.
  8. "Components of the REST/CoREST/histone deacetylase repressor complex are disrupted, modified, and translocated in HSV-1-infected cells."
    Gu H., Liang Y., Mandel G., Roizman B.
    Proc. Natl. Acad. Sci. U.S.A. 102:7571-7576(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH HUMAN RCOR1.
  9. "Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7."
    Boutell C., Canning M., Orr A., Everett R.D.
    J. Virol. 79:12342-12354(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  10. "Identification of a novel higher molecular weight isoform of USP7/HAUSP that interacts with the Herpes simplex virus type-1 immediate early protein ICP0."
    Antrobus R., Boutell C.
    Virus Res. 137:64-71(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HUMAN USP7, DEUBIQUITINATION BY HUMAN USP7.
  11. "A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses."
    Lilley C.E., Chaurushiya M.S., Boutell C., Landry S., Suh J., Panier S., Everett R.D., Stewart G.S., Durocher D., Weitzman M.D.
    EMBO J. 29:943-955(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  12. "Cellular localization of the herpes simplex virus ICP0 protein dictates its ability to block IRF3-mediated innate immune responses."
    Paladino P., Collins S.E., Mossman K.L.
    PLoS ONE 5:E10428-E10428(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION.
  13. "Comparison of the biological and biochemical activities of several members of the alphaherpesvirus ICP0 family of proteins."
    Everett R.D., Boutell C., McNair C., Grant L., Orr A.
    J. Virol. 84:3476-3487(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  14. "Viral E3 ubiquitin ligase-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain."
    Chaurushiya M.S., Lilley C.E., Aslanian A., Meisenhelder J., Scott D.C., Landry S., Ticau S., Boutell C., Yates J.R. III, Schulman B.A., Hunter T., Weitzman M.D.
    Mol. Cell 46:79-90(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH HUMAN RNF8, PHOSPHORYLATION AT THR-67, MUTAGENESIS OF THR-67.
  15. "Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein."
    Orzalli M.H., DeLuca N.A., Knipe D.M.
    Proc. Natl. Acad. Sci. U.S.A. 109:E3008-E3017(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  16. "Identification of TRIM27 as a novel degradation target of Herpes Simplex Virus 1 ICP0."
    Conwell S.E., White A.E., Harper J.W., Knipe D.M.
    J. Virol. 89:220-229(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HOST TRIM27.

Entry informationi

Entry nameiICP0_HHV11
AccessioniPrimary (citable) accession number: P08393
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1988
Last sequence update: August 1, 1988
Last modified: June 24, 2015
This is version 109 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.