P08393 (ICP0_HHV11) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	ICP0
Synonyms:	IE110

Organism

Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1) [Reference proteome]

Taxonomic identifier

10299 [NCBI]

Taxonomic lineage

Viruses › dsDNA viruses, no RNA stage › Herpesvirales › Herpesviridae › Alphaherpesvirinae › Simplexvirus › Human herpesvirus 1

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	775 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	RING-finger E3 ubiquitin ligase that plays an important regulatory role during the initial stages of lytic infection and the reactivation of quiescent HSV-1 genomes from latency. Enhances the localization of host CCND3 to ND10 bodies that serve as precursors of replication compartments to enable efficient viral replication. In conjunction with the ubiquitin-conjugating enzyme UBE2D1, degrades host PML and SP100, the major constituents of ND10 nuclear bodies. 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. 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. Additionally, ICP0 inhibits host IRF3 activation 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. Ref.8 Ref.9 Ref.11 Ref.12 Ref.13
Subunit structure	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). Ref.4 Ref.5 Ref.6 Ref.8 Ref.10 Ref.13
Subcellular location	Host cytoplasm. Host nucleus Ref.12.
Post-translational modification	Phosphorylated at Thr-67, leading to promote interaction with host RNF8. Ref.13 Auto-ubiquitinated. Deubiquitinated by host USP7; leading to stabilize it.
Sequence similarities	Contains 1 RING-type zinc finger.

Ontologies

Keywords
Biological process	Host-virus interaction Inhibition of host IFN-mediated response initiation by virus Inhibition of host IRF3 by virus Inhibition of host innate immune response by virus Inhibition of host mitotic exit 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
Cellular component	Host cytoplasm Host nucleus
Developmental stage	Early protein
Domain	Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Activator Ligase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	modulation by virus of host protein ubiquitination Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of protein catabolic process Traceable author statement Ref.7. Source: AgBase protein polyubiquitination Inferred from direct assay Ref.7. Source: AgBase regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW release from viral latency Traceable author statement Ref.7. Source: AgBase response to type I interferon Inferred from direct assay PubMed 16873258. Source: BHF-UCL suppression by virus of host IRF3 activity Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host exit from mitosis Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host type I interferon production Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	host cell cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell host cell nucleus Non-traceable author statement Ref.7. Source: UniProtKB
Molecular_function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW ubiquitin-protein ligase activity Inferred from direct assay Ref.7. Source: AgBase zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 775	775	E3 ubiquitin-protein ligase ICP0		PRO_0000056352
Regions
	Zinc finger	116 – 157	42	RING-type
	Compositional bias	233 – 243	11	Poly-Asp
	Compositional bias	305 – 308	4	Poly-Gly
	Compositional bias	558 – 568	11	Poly-Ser
Amino acid modifications
	Modified residue	67	1	Phosphothreonine; by host; by CK1 Ref.13
Experimental info
	Mutagenesis	67	1	T → A: Abolishes interaction host RNF8. Ref.13

Sequences

	Sequence		Length	Mass (Da)
	P08393 [UniParc]. Last modified August 1, 1988. Version 1. Checksum: DF38A1C539DAB15C	FASTA	775	78,457
	10 20 30 40 50 60 MEPRPGASTR RPEGRPQREP APDVWVFPCD RDLPDSSDSE AETEVGGRGD ADHHDDDSAS 70 80 90 100 110 120 EADSTDTELF ETGLLGPQGV DGGAVSGGSP PREEDPGSCG GAPPREDGGS DEGDVCAVCT 130 140 150 160 170 180 DEIAPHLRCD TFPCMHRFCI PCMKTWMQLR NTCPLCNAKL VYLIVGVTPS GSFSTIPIVN 190 200 210 220 230 240 DPQTRMEAEE AVRAGTAVDF IWTGNQRFAP RYLTLGGHTV RALSPTHPEP TTDEDDDDLD 250 260 270 280 290 300 DADYVPPAPR RTPRAPPRRG AAAPPVTGGA SHAAPQPAAA RTAPPSAPIG PHGSSNTNTT 310 320 330 340 350 360 TNSSGGGGSR QSRAAAPRGA SGPSGGVGVG VGVVEAEAGR PRGRTGPLVN RPAPLANNRD 370 380 390 400 410 420 PIVISDSPPA SPHRPPAAPM PGSAPRPGPP ASAAASGPAR PRAAVAPCVR APPPGPGPRA 430 440 450 460 470 480 PAPGAEPAAR PADARRVPQS HSSLAQAANQ EQSLCRARAT VARGSGGPGV EGGHGPSRGA 490 500 510 520 530 540 APSGAAPLPS AASVEQEAAV RPRKRRGSGQ ENPSPQSTRP PLAPAGAKRA ATHPPSDSGP 550 560 570 580 590 600 GGRGQGGPGT PLTSSAASAS SSSASSSSAP TPAGAASSAA GAASSSASAS SGGAVGALGG 610 620 630 640 650 660 RQEETSLGPR AASGPRGPRK CARKTRHAET SGAVPAGGLT RYLPISGVSS VVALSPYVNK 670 680 690 700 710 720 TITGDCLPIL DMETGNIGAY VVLVDQTGNM ATRLRAAVPG WSRRTLLPET AGNHVMPPEY 730 740 750 760 770 PTAPASEWNS LWMTPVGNML FDQGTLVGAL DFRSLRSRHP WSGEQGASTR DEGKQ

References

[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: AUTO-UBIQUITINATION.
[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]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X14112 Genomic DNA. Translation: CAA32336.1. X14112 Genomic DNA. Translation: CAA32293.1. X04614 Genomic DNA. Translation: CAA28285.1.
PIR	EDBE11. A29152.
RefSeq	NP_044601.1. NC_001806.1. NP_044660.1. NC_001806.1.
3D structure databases
ProteinModelPortal	P08393.
ModBase	Search...
Protein-protein interaction databases
IntAct	P08393. 2 interactions.
MINT	MINT-1345075.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	2703389. 2703390.
Phylogenomic databases
ProtClustDB	CLSP2510186.
Family and domain databases
Gene3D	3.30.40.10. 1 hit.
InterPro	IPR018957. Znf_C3HC4_RING-type. IPR001841. Znf_RING. IPR013083. Znf_RING/FYVE/PHD. IPR017907. Znf_RING_CS. [Graphical view]
Pfam	PF00097. zf-C3HC4. 1 hit. [Graphical view]
SMART	SM00184. RING. 1 hit. [Graphical view]
PROSITE	PS00518. ZF_RING_1. 1 hit. PS50089. ZF_RING_2. 1 hit. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

ICP0_HHV11

Accession

Primary (citable) accession number: P08393

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1988
Last sequence update:	August 1, 1988
Last modified:	April 3, 2013
This is version 92 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program