ID ICP0_HHV11 Reviewed; 775 AA. AC P08393; DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1988, sequence version 1. DT 27-MAR-2024, entry version 155. DE RecName: Full=E3 ubiquitin-protein ligase ICP0; DE EC=2.3.2.27 {ECO:0000269|PubMed:32001251}; DE AltName: Full=Alpha-0 protein; DE AltName: Full=Immediate-early protein IE110; DE AltName: Full=RING-type E3 ubiquitin transferase ICP0 {ECO:0000305}; DE AltName: Full=Trans-acting transcriptional protein ICP0; DE AltName: Full=VMW110; GN Name=ICP0; Synonyms=IE110; OS Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1). OC Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes; OC Herpesvirales; Orthoherpesviridae; Alphaherpesvirinae; Simplexvirus; OC Simplexvirus humanalpha1; Human herpesvirus 1. OX NCBI_TaxID=10299; OH NCBI_TaxID=9606; Homo sapiens (Human). RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2839594; DOI=10.1099/0022-1317-69-7-1531; RA McGeoch D.J., Dalrymple M.A., Davison A.J., Dolan A., Frame M.C., McNab D., RA Perry L.J., Scott J.E., Taylor P.; RT "The complete DNA sequence of the long unique region in the genome of RT herpes simplex virus type 1."; RL J. Gen. Virol. 69:1531-1574(1988). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3023529; DOI=10.1099/0022-1317-67-11-2365; RA Perry L.J., Rixon F.J., Everett R.D., Frame M.C., McGeoch D.J.; RT "Characterization of the IE110 gene of herpes simplex virus type 1."; RL J. Gen. Virol. 67:2365-2380(1986). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2846760; DOI=10.1099/0022-1317-69-11-2831; RA Perry L.J., McGeoch D.J.; RT "The DNA sequences of the long repeat region and adjoining parts of the RT long unique region in the genome of herpes simplex virus type 1."; RL J. Gen. Virol. 69:2831-2846(1988). RN [4] RP INTERACTION WITH HUMAN CENPA. RX PubMed=11053442; DOI=10.1074/jbc.m008547200; RA Lomonte P., Sullivan K.F., Everett R.D.; RT "Degradation of nucleosome-associated centromeric histone H3-like protein RT CENP-A induced by herpes simplex virus type 1 protein ICP0."; RL J. Biol. Chem. 276:5829-5835(2001). RN [5] RP INTERACTION WITH HUMAN CDC34. RX PubMed=11447293; DOI=10.1073/pnas.161283098; RA Van Sant C., Hagglund R., Lopez P., Roizman B.; RT "The infected cell protein 0 of herpes simplex virus 1 dynamically RT interacts with proteasomes, binds and activates the cdc34 E2 ubiquitin- RT conjugating enzyme, and possesses in vitro E3 ubiquitin ligase activity."; RL Proc. Natl. Acad. Sci. U.S.A. 98:8815-8820(2001). RN [6] RP INTERACTION WITH HUMAN USP7. RX PubMed=14506283; DOI=10.1074/jbc.m307200200; RA Holowaty M.N., Sheng Y., Nguyen T., Arrowsmith C., Frappier L.; RT "Protein interaction domains of the ubiquitin-specific protease, RT USP7/HAUSP."; RL J. Biol. Chem. 278:47753-47761(2003). RN [7] RP AUTOUBIQUITINATION. RX PubMed=15247261; DOI=10.1074/jbc.m402885200; RA Canning M., Boutell C., Parkinson J., Everett R.D.; RT "A RING finger ubiquitin ligase is protected from autocatalyzed RT ubiquitination and degradation by binding to ubiquitin-specific protease RT USP7."; RL J. Biol. Chem. 279:38160-38168(2004). RN [8] RP FUNCTION, AND INTERACTION WITH HUMAN RCOR1. RX PubMed=15897453; DOI=10.1073/pnas.0502658102; RA Gu H., Liang Y., Mandel G., Roizman B.; RT "Components of the REST/CoREST/histone deacetylase repressor complex are RT disrupted, modified, and translocated in HSV-1-infected cells."; RL Proc. Natl. Acad. Sci. U.S.A. 102:7571-7576(2005). RN [9] RP FUNCTION. RX PubMed=16160161; DOI=10.1128/jvi.79.19.12342-12354.2005; RA Boutell C., Canning M., Orr A., Everett R.D.; RT "Reciprocal activities between herpes simplex virus type 1 regulatory RT protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease RT USP7."; RL J. Virol. 79:12342-12354(2005). RN [10] RP INTERACTION WITH HUMAN USP7, AND DEUBIQUITINATION BY HUMAN USP7. RX PubMed=18590780; DOI=10.1016/j.virusres.2008.05.017; RA Antrobus R., Boutell C.; RT "Identification of a novel higher molecular weight isoform of USP7/HAUSP RT that interacts with the Herpes simplex virus type-1 immediate early protein RT ICP0."; RL Virus Res. 137:64-71(2008). RN [11] RP FUNCTION. RX PubMed=20075863; DOI=10.1038/emboj.2009.400; RA Lilley C.E., Chaurushiya M.S., Boutell C., Landry S., Suh J., Panier S., RA Everett R.D., Stewart G.S., Durocher D., Weitzman M.D.; RT "A viral E3 ligase targets RNF8 and RNF168 to control histone RT ubiquitination and DNA damage responses."; RL EMBO J. 29:943-955(2010). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=20454685; DOI=10.1371/journal.pone.0010428; RA Paladino P., Collins S.E., Mossman K.L.; RT "Cellular localization of the herpes simplex virus ICP0 protein dictates RT its ability to block IRF3-mediated innate immune responses."; RL PLoS ONE 5:E10428-E10428(2010). RN [13] RP FUNCTION. RX PubMed=20106921; DOI=10.1128/jvi.02544-09; RA Everett R.D., Boutell C., McNair C., Grant L., Orr A.; RT "Comparison of the biological and biochemical activities of several members RT of the alphaherpesvirus ICP0 family of proteins."; RL J. Virol. 84:3476-3487(2010). RN [14] RP FUNCTION, INTERACTION WITH HUMAN RNF8, PHOSPHORYLATION AT THR-67, AND RP MUTAGENESIS OF THR-67. RX PubMed=22405594; DOI=10.1016/j.molcel.2012.02.004; RA Chaurushiya M.S., Lilley C.E., Aslanian A., Meisenhelder J., Scott D.C., RA Landry S., Ticau S., Boutell C., Yates J.R. III, Schulman B.A., Hunter T., RA Weitzman M.D.; RT "Viral E3 ubiquitin ligase-mediated degradation of a cellular E3: viral RT mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain."; RL Mol. Cell 46:79-90(2012). RN [15] RP FUNCTION. RX PubMed=23027953; DOI=10.1073/pnas.1211302109; RA Orzalli M.H., DeLuca N.A., Knipe D.M.; RT "Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection RT and degradation of IFI16 by the viral ICP0 protein."; RL Proc. Natl. Acad. Sci. U.S.A. 109:E3008-E3017(2012). RN [16] RP INTERACTION WITH HOST ZBP1. RX PubMed=23283962; DOI=10.1128/jvi.02860-12; RA Pham T.H., Kwon K.M., Kim Y.E., Kim K.K., Ahn J.H.; RT "DNA sensing-independent inhibition of herpes simplex virus 1 replication RT by DAI/ZBP1."; RL J. Virol. 87:3076-3086(2013). RN [17] RP INTERACTION WITH HOST TRIM27. RX PubMed=25320289; DOI=10.1128/jvi.02635-14; RA Conwell S.E., White A.E., Harper J.W., Knipe D.M.; RT "Identification of TRIM27 as a novel degradation target of Herpes Simplex RT Virus 1 ICP0."; RL J. Virol. 89:220-229(2015). RN [18] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH HOST MORC3. RX PubMed=27440897; DOI=10.1128/jvi.00621-16; RA Sloan E., Orr A., Everett R.D.; RT "MORC3, a Component of PML Nuclear Bodies, Has a Role in Restricting Herpes RT Simplex Virus 1 and Human Cytomegalovirus."; RL J. Virol. 90:8621-8633(2016). RN [19] RP FUNCTION, AND INTERACTION WITH HOST MORC3. RX PubMed=34759314; DOI=10.1038/s41586-021-04054-5; RA Gaidt M.M., Morrow A., Fairgrieve M.R., Karr J.P., Yosef N., Vance R.E.; RT "Self-guarding of MORC3 enables virulence factor-triggered immunity."; RL Nature 600:138-142(2021). RN [20] {ECO:0007744|PDB:6JXU, ECO:0007744|PDB:6JXV, ECO:0007744|PDB:6JXW, ECO:0007744|PDB:6JXX} RP STRUCTURE BY NMR OF 355-374, FUNCTION, PHOSPHORYLATION BY HOST CK1 AND RP CHEK2, AND CATALYTIC ACTIVITY. RX PubMed=32001251; DOI=10.1016/j.jmb.2020.01.021; RA Hembram D.S.S., Negi H., Biswas P., Tripathi V., Bhushan L., Shet D., RA Kumar V., Das R.; RT "The Viral SUMO-Targeted Ubiquitin Ligase ICP0 is Phosphorylated and RT Activated by Host Kinase Chk2."; RL J. Mol. Biol. 432:1952-1977(2020). CC -!- FUNCTION: SUMO-targeted ubiquitin ligase that plays an essential role CC in nuclear antiviral defense evasion triggered by dsDNA viruses CC (PubMed:32001251). Acts during the initial stages of lytic infection CC and the reactivation of latent viral genome. Prevents the antiviral CC effect of nuclear bodies by degrading host PML, SP100 and MORC3 CC (PubMed:27440897, PubMed:34759314). Prevents antiviral response to CC viral DNA induced by IFI16 by degrading it. Additionally, inhibits host CC IRF3 nuclear signaling to prevent interferon production by the infected CC cells. Interestingly, the E3 ubiquitin ligase activity associated with CC the RING finger domain does not seem to be directly required to inhibit CC the activation of IRF3 but instead plays a critical role in modulating CC the cellular localization of ICP0. Upon reactivation of latent genome, CC suppresses the silencing of viral DNA by dissociating either HDAC1 or CC HDAC2 from the HDAC-RCOR1-REST-KDM1A complex localized at the ND10 CC structures and causes their dispersal. Two cellular histone ubiquitin CC ligases RNF8 and RNF168 are also targeted by ICP0 for degradation, CC leading to a loss of ubiquitinated forms of H2A, a relief of CC transcriptional repression, and the activation of latent viral genomes. CC Enhances the localization of host CCND3 to ND10 bodies that serve as CC precursors of replication compartments to enable efficient viral CC replication. Like many RING-finger E3 ubiquitin ligases, ICP0 can CC induce its own ubiquitination, an activity that promotes its CC instability due to its targeting to the 26S proteasome for degradation. CC ICP0 restricts this process by recruiting the cellular ubiquitin- CC specific protease USP7 that cleaves the anchored ubiquitin chains from CC ICP0, thereby promoting its stabilization. CC {ECO:0000269|PubMed:15897453, ECO:0000269|PubMed:16160161, CC ECO:0000269|PubMed:20075863, ECO:0000269|PubMed:20106921, CC ECO:0000269|PubMed:20454685, ECO:0000269|PubMed:22405594, CC ECO:0000269|PubMed:23027953, ECO:0000269|PubMed:27440897, CC ECO:0000269|PubMed:34759314}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; CC -!- SUBUNIT: Interacts directly with human RCOR1/CoREST protein, leading to CC the disruption of the human BHC corepressor complex (PubMed:15897453). CC Interacts with human CENPA, leading to its degradation CC (PubMed:11053442). Interacts with human USP7; this interaction CC modulates ICP0 stability (PubMed:14506283, PubMed:18590780). Interacts CC with human CDC34 (PubMed:11447293). Interacts (when phosphorylated) CC with human RNF8 (via FHA domain) (PubMed:22405594). Interacts with CC human TRIM27 (PubMed:25320289). Interacts with human ZBP1 CC (PubMed:23283962). Interacts with host MORC3; this interaction promotes CC the degradation of host MORC3 (PubMed:27440897, PubMed:34759314). CC {ECO:0000269|PubMed:11053442, ECO:0000269|PubMed:11447293, CC ECO:0000269|PubMed:14506283, ECO:0000269|PubMed:15897453, CC ECO:0000269|PubMed:18590780, ECO:0000269|PubMed:22405594, CC ECO:0000269|PubMed:23283962, ECO:0000269|PubMed:25320289, CC ECO:0000269|PubMed:27440897, ECO:0000269|PubMed:34759314}. CC -!- INTERACTION: CC P08393; P30281: CCND3; Xeno; NbExp=3; IntAct=EBI-6148881, EBI-375013; CC P08393; O15379: HDAC3; Xeno; NbExp=3; IntAct=EBI-6148881, EBI-607682; CC P08393; P56524: HDAC4; Xeno; NbExp=3; IntAct=EBI-6148881, EBI-308629; CC P08393; Q9UQL6: HDAC5; Xeno; NbExp=3; IntAct=EBI-6148881, EBI-715576; CC P08393; Q8WUI4: HDAC7; Xeno; NbExp=3; IntAct=EBI-6148881, EBI-1048378; CC P08393; Q9UKL0: RCOR1; Xeno; NbExp=2; IntAct=EBI-6148881, EBI-926563; CC P08393; Q93008: USP9X; Xeno; NbExp=3; IntAct=EBI-6148881, EBI-302524; CC -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000269|PubMed:20454685}. CC Host nucleus {ECO:0000269|PubMed:20454685}. CC -!- PTM: Phosphorylated at Thr-67, leading to promote interaction with host CC RNF8 (PubMed:22405594). Phosphorylated by host CHEK2; leading to CC increased SUMO-targeted ubiquitin ligase activity of ICP0 CC (PubMed:32001251). {ECO:0000269|PubMed:22405594, CC ECO:0000269|PubMed:32001251}. CC -!- PTM: Auto-ubiquitinated. Deubiquitinated by host USP7; leading to CC stabilize it. {ECO:0000269|PubMed:15247261, CC ECO:0000269|PubMed:18590780}. CC -!- SIMILARITY: Belongs to the simplexviruses ICp0 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X14112; CAA32336.1; -; Genomic_DNA. DR EMBL; X14112; CAA32293.1; -; Genomic_DNA. DR EMBL; X04614; CAA28285.1; -; Genomic_DNA. DR PIR; A29152; EDBE11. DR RefSeq; YP_009137074.1; NC_001806.2. DR RefSeq; YP_009137133.1; NC_001806.2. DR PDB; 4WPH; X-ray; 2.92 A; C/D=617-627. DR PDB; 4WPI; X-ray; 3.40 A; C/D=617-627. DR PDB; 5C56; X-ray; 2.69 A; B=613-633. DR PDB; 6JXU; NMR; -; B=357-368. DR PDB; 6JXV; NMR; -; B=355-374. DR PDB; 6JXW; NMR; -; B=355-374. DR PDB; 6JXX; NMR; -; B=355-374. DR PDBsum; 4WPH; -. DR PDBsum; 4WPI; -. DR PDBsum; 5C56; -. DR PDBsum; 6JXU; -. DR PDBsum; 6JXV; -. DR PDBsum; 6JXW; -. DR PDBsum; 6JXX; -. DR SMR; P08393; -. DR BioGRID; 971426; 20. DR BioGRID; 971427; 25. DR DIP; DIP-42446N; -. DR IntAct; P08393; 21. DR MINT; P08393; -. DR iPTMnet; P08393; -. DR GeneID; 2703389; -. DR GeneID; 2703390; -. DR KEGG; vg:2703389; -. DR KEGG; vg:2703390; -. DR Proteomes; UP000009294; Genome. DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0042025; C:host cell nucleus; NAS:UniProtKB. DR GO; GO:0019033; C:viral tegument; IDA:CACAO. DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProt. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:AgBase. DR GO; GO:0039648; P:modulation by symbiont of host protein ubiquitination; IEA:UniProtKB-KW. DR GO; GO:0039593; P:peturbation by virus of host exit from mitosis; IEA:UniProtKB-KW. DR GO; GO:0045732; P:positive regulation of protein catabolic process; TAS:AgBase. DR GO; GO:0000209; P:protein polyubiquitination; IDA:AgBase. DR GO; GO:0019046; P:release from viral latency; TAS:AgBase. DR GO; GO:0034340; P:response to type I interferon; IDA:BHF-UCL. DR GO; GO:0039501; P:suppression by virus of host type I interferon production; IDA:UniProt. DR GO; GO:0039548; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity; IDA:UniProtKB. DR GO; GO:0075342; P:symbiont-mediated disruption of host cell PML body; IDA:UniProtKB. DR CDD; cd23130; RING-HC_EHV1-like; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR018957; Znf_C3HC4_RING-type. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. DR Pfam; PF00097; zf-C3HC4; 1. DR SMART; SM00184; RING; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Activator; DNA-binding; Early protein; Host cytoplasm; KW Host nucleus; Host-virus interaction; KW Inhibition of host innate immune response by virus; KW Inhibition of host IRF3 by virus; Inhibition of host mitotic exit by virus; KW Inhibition of host RLR pathway by virus; Metal-binding; KW Modulation of host cell cycle by virus; KW Modulation of host ubiquitin pathway by viral E3 ligase; KW Modulation of host ubiquitin pathway by virus; Phosphoprotein; KW Reference proteome; Transcription; Transcription regulation; Transferase; KW Ubl conjugation; Ubl conjugation pathway; Viral immunoevasion; KW Viral latency; Viral reactivation from latency; Zinc; Zinc-finger. FT CHAIN 1..775 FT /note="E3 ubiquitin-protein ligase ICP0" FT /id="PRO_0000056352" FT ZN_FING 116..157 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT REGION 1..112 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 221..636 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..18 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 33..60 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 289..310 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 368..394 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 407..425 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 439..456 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 548..592 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 67 FT /note="Phosphothreonine; by host; by CK1" FT /evidence="ECO:0000269|PubMed:22405594, FT ECO:0000269|PubMed:32001251" FT MUTAGEN 67 FT /note="T->A: Abolishes interaction host RNF8." FT /evidence="ECO:0000269|PubMed:22405594" FT STRAND 359..363 FT /evidence="ECO:0007829|PDB:6JXU" SQ SEQUENCE 775 AA; 78457 MW; DF38A1C539DAB15C CRC64; MEPRPGASTR RPEGRPQREP APDVWVFPCD RDLPDSSDSE AETEVGGRGD ADHHDDDSAS EADSTDTELF ETGLLGPQGV DGGAVSGGSP PREEDPGSCG GAPPREDGGS DEGDVCAVCT DEIAPHLRCD TFPCMHRFCI PCMKTWMQLR NTCPLCNAKL VYLIVGVTPS GSFSTIPIVN DPQTRMEAEE AVRAGTAVDF IWTGNQRFAP RYLTLGGHTV RALSPTHPEP TTDEDDDDLD DADYVPPAPR RTPRAPPRRG AAAPPVTGGA SHAAPQPAAA RTAPPSAPIG PHGSSNTNTT TNSSGGGGSR QSRAAAPRGA SGPSGGVGVG VGVVEAEAGR PRGRTGPLVN RPAPLANNRD PIVISDSPPA SPHRPPAAPM PGSAPRPGPP ASAAASGPAR PRAAVAPCVR APPPGPGPRA PAPGAEPAAR PADARRVPQS HSSLAQAANQ EQSLCRARAT VARGSGGPGV EGGHGPSRGA APSGAAPLPS AASVEQEAAV RPRKRRGSGQ ENPSPQSTRP PLAPAGAKRA ATHPPSDSGP GGRGQGGPGT PLTSSAASAS SSSASSSSAP TPAGAASSAA GAASSSASAS SGGAVGALGG RQEETSLGPR AASGPRGPRK CARKTRHAET SGAVPAGGLT RYLPISGVSS VVALSPYVNK TITGDCLPIL DMETGNIGAY VVLVDQTGNM ATRLRAAVPG WSRRTLLPET AGNHVMPPEY PTAPASEWNS LWMTPVGNML FDQGTLVGAL DFRSLRSRHP WSGEQGASTR DEGKQ //