HHV Infected Cell Polypeptide 0 (ICP0)

Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage is known as the "immediate-early" or "α" ("alpha") phase of viral gene expression. cite web|title=Herpes simplex virus Research|url=http://www.dbc.uci.edu/~faculty/wagner/hsv4f.html|author=Dr. Edward K. Wagner|accessed-date=Oct 25 2007] During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus of the infected host cell. Here, ICP0 promotes transcription from viral genes, disrupts structures in the nucleus known as nuclear dots or promyelocytic leukemia (PML) nuclear bodies, and alters the expression of host and viral genes in combination with a neuron specific protein. At later stages of cellular infection, ICP0 relocates to the cell cytoplasm to be incorporated into new virion particles.cite journal
title=Herpes simplex virus type 1 immediate-early protein ICP27 is required for efficient incorporation of ICP0 and ICP4 into virions
journal=Journal of virology
date=2008 Jan
author = Sedlackova L, Rice SA
volume=82
issue=1
pages=268–77
pmid=17959681
doi=10.1128/JVI.01588-07]

History and background

ICP0 was identified as an immediate-early polypeptide product of Herpes simplex virus-1 (HSV-1) infection in 1976.cite journal
title=Control of protein synthesis in herpesvirus-infected cells: analysis of the polypeptides induced by wild type and sixteen temperature-sensitive mutants of HSV strain 17
journal=Journal of General Virology
date=1976 Jun
author = Marsden HS, Crombie IK, Subak-Sharpe JH
volume=31
issue=3
pages=347–72
pmid=180249(Free full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=180249&db=pubmed&url=http://vir.sgmjournals.org/cgi/pmidlookup?view=long&pmid=180249] )] The gene, in HSV-1, from which ICP0 is produced is known as "HSV-1 α0" ("alpha zero") , "Immediate Early (IE) gene 1", or simply as the "HSV-1 ICP0 gene". The HSV-1 ICP0 gene was characterized and sequenced in 1986.cite journal
title=Characterization of the IE110 gene of herpes simplex virus type 1
journal=Journal of General Virology
date=1986 Nov
author = Perry LJ, Rixon FJ, Everett RD, Frame MC, McGeoch DJ
volume=67 ( Pt 11)
pages=2365–80
pmid=3023529(Free full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=3023529&db=pubmed&url=http://vir.sgmjournals.org/cgi/pmidlookup?view=long&pmid=3023529] )] This sequence predicted a 775 amino acid sequence with a molecular weight of 78.5 KDa.cite web|title=Protein ICP0_HHV11|author=UniProt Consortium|url=http://www.ebi.uniprot.org/uniprot-srv/uniProtView.do?proteinId=ICP0_HHV11&pager.offset=0|accessed-date=28 Oct 2007|date=24 Jul 2007] At the time of gene isolation, ICP0 was known as IE110 as gel electrophoresis experiments performed prior to obtaining the gene sequence indicated the ICP0 protein weighed 110 kDa. Post-translational modifications, such as phosphorylation or sumoylation, were presumed to account for the actual protein size appearing 30 kDa larger than that of the predicted amino acid sequence.

Functions

Transcription

In HSV-1 infected cells, ICP0 activates transcription of many viral and cellular genes. It acts synergistically HSV-1 immediate early (IE) protein, ICP4, and is essential for reactivation of latent herpes virus and viral replication.cite journal |author=Everett RD |title=ICP0, a regulator of herpes simplex virus during lytic and latent infection |journal=Bioessays |volume=22 |issue=8 |pages=761–70 |year=2000 |pmid=10918307 |doi=10.1002/1521-1878(200008)22:8<761::AID-BIES10>3.0.CO;2-A |doilabel=10.1002/1521-1878(200008)22:8761::AID-BIES103.0.CO;2-A]

Degradation of antiviral pathways

ICP0 is responsible for overcoming a variety of cellular antiviral responses. After translocating to the nucleus early in infection, ICP0 promotes degradation of many cellular antiviral genes, including those for nuclear body-associated proteins promyelocytic leukemia protein (PML) and Sp100, causing disruption of PML nuclear bodies and reduced cellular antiviral capacity.cite journal |author=Everett RD, Rechter S, Papior P, Tavalai N, Stamminger T, Orr A |title=PML contributes to a cellular mechanism of repression of herpes simplex virus type 1 infection that is inactivated by ICP0 |journal=J. Virol. |volume=80 |issue=16 |pages=7995–8005 |year=2006 |pmid=16873256 |doi=10.1128/JVI.00734-06 |url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=16873256] cite journal |author=Gu H, Roizman B |title=The degradation of promyelocytic leukemia and Sp100 proteins by herpes simplex virus 1 is mediated by the ubiquitin-conjugating enzyme UbcH5a |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=15 |pages=8963–8 |year=2003 |pmid=12855769 |doi=10.1073/pnas.1533420100 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12855769] ICP0 also inhibits the activity of IFN regulatory factors (IRF3) and IRF7, which are key transcription factors that induce production of antiviral cytokines called interferons.cite journal |author=Lin R, Noyce RS, Collins SE, Everett RD, Mossman KL |title=The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes |journal=J. Virol. |volume=78 |issue=4 |pages=1675–84 |year=2004 |pmid=14747533 |doi= |url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=14747533] Barriers to viral replication induced by interferons can also be overcome by the action of ICP0.cite journal |author=Mossman K |title=Analysis of anti-interferon properties of the herpes simplex virus type I ICP0 protein |journal=Methods Mol. Med. |volume=116 |issue= |pages=195–205 |year=2005 |pmid=16000863 |doi=10.1385/1-59259-939-7:195 |url=http://biomed.humanapress.com/ChapterDetail.pasp?medline=1-59259-939-7:195] This function of ICP0 also prevents production of RNase L, an enzyme that degrades single-stranded viral and cellular RNAs and induces host cell apoptosis in virus infected cells.cite journal
title=ICP0 prevents RNase L-independent rRNA cleavage in herpes simplex virus type 1-infected cells
journal=Journal of virology
date=2006 Jan
volume=80
issue=1
pages=218–25
pmid=16352546
doi=10.1128/JVI.80.1.218-225.2006(Free full-text article: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16352546] )]

Interaction with host cell SUMO-1 protein and disruption PML Nuclear Bodies

Small ubiquitin-related modifier 1 (SUMO-1) is a protein produced by human cells that is involved in the modification of many proteins, including human PML protein.cite journal
title=Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus
journal=The EMBO journal
date=1998 Jan 2
volume=17
issue=1
pages=61–70
pmid=9427741
doi=10.1093/emboj/17.1.61(Free full-text article: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9427741] )] cite journal
title=Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1
journal=The Journal of cell biology
date=1997 Dec 29
volume=139
issue=7
pages=1621–34
pmid=9412458
doi=10.1083/jcb.139.7.1621] cite journal |author=Kroetz MB |title=SUMO: a ubiquitin-like protein modifier |journal=Yale J Biol Med |volume=78 |issue=4 |pages=197–201 |year=2005 |pmid=16720014 |doi= |url=http://openurl.ingenta.com/content/nlm?genre=article&issn=0044-0086&volume=78&issue=4&spage=197&aulast=Kroetz] HSV-1 ICP0 and several of its homologs in other herpes viruses bind to SUMO-1 in a manner similar to endogenous proteins, causing depletion of SUMO-1, and disruption of nuclear bodies.cite journal
title=Ability of the human cytomegalovirus IE1 protein to modulate sumoylation of PML correlates with its functional activities in transcriptional regulation and infectivity in cultured fibroblast cells
journal=Journal of virology
date=2004 Jun
volume=78
issue=12
pages=6527–42
pmid=15163746
doi=10.1128/JVI.78.12.6527-6542.2004(Free full-text article: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15163746] )] cite journal
title=Proteasome-independent disruption of PML oncogenic domains (PODs), but not covalent modification by SUMO-1, is required for human cytomegalovirus immediate-early protein IE1 to inhibit PML-mediated transcriptional repression
journal=Journal of virology
date=2001 Nov
volume=75
issue=22
pages=10683–95
pmid=11602710
doi=10.1128/JVI.75.22.10683-10695.2001(Free full-text article: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11602710] )] cite journal
title=Herpes simplex virus 1 ICP0 co-localizes with a SUMO-specific protease
journal=The Journal of general virology
date=2002 Dec
volume=83
issue=Pt 12
pages=2951–64
pmid=12466471] cite journal
title=The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1
journal=Experimental cell research
date=1996 Nov 25
volume=229
issue=1
pages=155–8
pmid=8940259
doi=10.1006/excr.1996.0353] cite journal
title=Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption
journal=Journal of virology
date=1999 Jun
volume=73
issue=6
pages=5137–43
pmid=10233977(Free full-text article: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10233977] )] cite journal
title=PML residue lysine 160 is required for the degradation of PML induced by herpes simplex virus type 1 regulatory protein ICP0
journal=Journal of virology
date=2003 Aug
volume=77
issue=16
pages=8686–94
pmid=12885887
doi=10.1128/JVI.77.16.8686-8694.2003(Free full-text article: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12885887] )]

Interaction with neuron-differentiating protein NRSF and protein cofactor coREST

ICP0 interacts with a human protein, known as Neuronal Restrictive Silencer Factor (NRSF) or RE1-silencing transcription factor (REST)Neuronal Restrictive Silencer Factor (NRSF) is also known as Repressor Element-1-Silencing Transcription factor (REST) and X2 Box Repressor (XBR):

cite web|url=http://www.ebi.uniprot.org/entry/Q13127-2|title=Protein REST_HUMAN|author=UniProt Consortium|date=11 Sep 2007|accessed-date=28 Oct 2007] that regulates differences in gene expression between cells of neuronal or non-neuronal origin; NRSF is found in non-neuronal cells but not in fully differentiated neurons. This interaction is attributed to the partial similarity of ICP0 to the human protein CoREST, also called REST corepressor 1 (RCOR1),cite journal
title=Components of the REST/CoREST/histone deacetylase repressor complex are disrupted, modified, and translocated in HSV-1-infected cells
journal=Proc Natl Acad Sci U S A
date=2005 May 24
author = Gu H, Liang Y, Mandel G, Roizman B
volume=102
issue=21
pages=7571–6
pmid=15897453
doi=10.1073/pnas.0502658102(Free full-text article: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15897453] )] which combines with NRSF to repress expression of neuronal genes in non-neuronal cells.cite journal
title=CoREST: a functional corepressor required for regulation of neural-specific gene expression
journal=Proc Natl Acad Sci U S A
date=1999 Aug 17
author = Andres ME, Burger C, Peral-Rubio MJ, Battaglioli E, Anderson ME, Grimes J, Dallman J, Ballas N, Mandel G
volume=96
issue=17
pages=9873–8
pmid=10449787
doi=10.1073/pnas.96.17.9873(Free full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3494&itool=AbstractPlus-nondef&uid=10449787&db=pubmed&url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10449787] )] cite journal
title=A common silencer element in the SCG10 and type II Na+ channel genes binds a factor present in nonneuronal cells but not in neuronal cells
journal=Neuron
date=1992 Jul
author = Mori N, Schoenherr C, Vandenbergh DJ, Anderson DJ
volume=9
issue=1
pages=45–54
pmid=1321646
doi=10.1016/0896-6273(92)90219-4]

Although the full NRSF protein is not typically found in neurons, truncated forms of NRSF are produced that selectively control the expression of certain neurotransmitter channels in specialized neurons.cite journal
title=Regulation of the cholinergic gene locus by the repressor element-1 silencing transcription factor/neuron restrictive silencer factor (REST/NRSF)
journal=Life Sci
date=2004 Mar 19
author = Shimojo M, Hersh LB
volume=74
issue=18
pages=2213–25
pmid=15017977
doi=10.1016/j.lfs.2003.08.045] Combination of ICP0 with these NRSF-like neuronal factors may silence herpes genes in neurons, blocking the production of other immediate-early genes such as ICP4 and reducing production of ICP22.cite journal
title=Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification
journal=Virol J
date=2007 Jun 7
author = Pinnoji RC, Bedadala GR, George B, Holland TC, Hill JM, Hsia SC
volume=4
pages=56
pmid=17555596(Free full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3494&itool=AbstractPlus-nondef&uid=17555596&db=pubmed&url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17555596] )] The repressed production of immediate-early HSV genes may contribute to the establishment of latency during infection with herpes viruses.

CoREST and NRSF combine with another cellular protein, histone deacetylase-1 (HDAC) to form a HDAC/CoREST/NRSF complex. This complex silences production of the HSV-1 protein ICP4 by interfering with chromatin remodeling of the viral DNA that is necessary to allow viral gene transcription; it deacetylates histones associated with viral DNA in viral chromatin. Furthermore, an NRSF-binding region is located between the viral genes expressing proteins ICP4 and ICP22. ICP0 interacts with coREST, dissociating HDAC1 from CoREST/NRSF in the HDAC/CoREST/NRSF complex and preventing the silencing of the HSV genome in non-neuronal cells.cite journal
title=Herpes simplex virus-infected cell protein 0 blocks the silencing of viral DNA by dissociating histone deacetylases from the CoREST REST complex
journal=Proc Natl Acad Sci U S A
date=2007 Oct 23
author = Gu H, Roizman B
volume=104
issue=43
pages=17134–9
pmid=17939992
doi=10.1073/pnas.0707266104(Subscription full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=17939992&db=pubmed&url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17939992] )]

Suppression of ICP0 activity

Interaction with latency-associated RNA transcript (LAT)

During latent infection a viral RNA transcript inhibits expression of the herpes virus ICP0 gene via an antisense RNA mechanism.A report that the 2.0-kb LAT intron terminates at the 5' end with a 750-base RNA that is an antisense complement for the ICP0 gene α0:

cite journal
title=Herpes simplex virus latency-associated transcript is a stable intron
journal=Proceedings of the National Academy of Science (USA)
date=1991 Feb 1
author = Farrell MJ, Dobson AT, Feldman LT
volume=88
issue=3
pages=790–4
pmid=1846963
doi=10.1073/pnas.88.3.790 (Free full-text article: [http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=50899&pageindex=1] )] The RNA transcript is produced by the virus and accumulates in host cells during latent infection; it is known as Latency Associated Transcript (LAT). A "chromatin insulator" region between promoters of the LAT and ICP0 genes of the HSV-1 genome may allow for the independent regulation of their expression.cite journal
title=CTCF-dependent chromatin boundary element between the latency-associated transcript and ICP0 promoters in the herpes simplex virus type 1 genome
journal=J Virol
date=2007 May
author = Chen Q, Lin L, Smith S, Huang J, Berger SL, Zhou J
volume=81
issue=10
pages=5192–201
pmid=17267480
doi=10.1128/JVI.02447-06(Free full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3494&itool=AbstractPlus-nondef&uid=17267480&db=pubmed&url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17267480] )]

Homologs across Herpes virus species

The ICP0 gene and protein from HSV-1 have orthologs in related viruses from the herpes virus family. HSV-2 ICP0 is predicted to produce a polypeptide of 825 amino acids with a predicted molecular weight of 81986 Da, and 61.5% amino acid sequence similarity to HSV-1 ICP0.cite web|title=Protein ICP0_HHV2H|author=UniProt Consortium|url=http://www.ebi.uniprot.org/uniprot-srv/uniProtView.do?proteinId=ICP0_HHV2H&pager.offset=0|date=24 Jul 2007|accessed-date=28 oct 2007] cite journal
title=Comparative sequence analysis of the long repeat regions and adjoining parts of the long unique regions in the genomes of herpes simplex viruses types 1 and 2
journal=Journal of General Virology
date=1991 Dec
author = McGeoch DJ, Cunningham C, McIntyre G, Dolan A
volume=72 ( Pt 12)
pages=3057–75
pmid=1662697(Free full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=1662697&db=pubmed&url=http://vir.sgmjournals.org/cgi/pmidlookup?view=long&pmid=1662697] )] Simian varicella virus (SVV) is a varicellovirus that, like HSV-1 and HSV-2, belongs to the alphaherpesvirinae subfamily of herpes viruses. SVV expresses an HSV-1 LAT ortholog known as SVV LAT, and an HSV-1 ICP0 ortholog known as SVV ORF-61 (Open Reading Frame 61).cite journal
title=Simian varicella virus expresses a latency-associated transcript that is antisense to open reading frame 61 (ICP0) mRNA in neural ganglia of latently infected monkeys
journal=Journal of Virology
date=2007 Aug
author = Ou Y, Davis KA, Traina-Dorge V, Gray WL
volume=81
issue=15
pages=8149–56
pmid=17507490
doi=10.1128/JVI.00407-07] Varicella Zoster Virus (VZV) is another varicellovirus in which a homolog of HSV-1 ICP0 gene has been identified; VSV ORF-61 is a partial homolog and a functional replacement for HSV-1 ICP0 gene.cite journal
title=Varicella-zoster virus open reading frame 61 protein is functionally homologous to herpes simplex virus type 1 ICP0
journal=Journal of Virology
date=1992 Dec
author = Moriuchi H, Moriuchi M, Smith HA, Straus SE, Cohen JI
volume=66
issue=12
pages=7303–8
pmid=1366099(Free full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=1366099&db=pubmed&url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=1366099] )] cite journal
title=Varicella-zoster virus (VZV) open reading frame 61 protein transactivates VZV gene promoters and enhances the infectivity of VZV DNA
journal=Journal of Virology
date=1993 Jul
author = Moriuchi H, Moriuchi M, Straus SE, Cohen JI
volume=67
issue=7
pages=4290–5
pmid=8389928(Free full-text article: [http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=8389928&db=pubmed&url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=8389928] )]

References