Structure of the ring-finger domain of 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.[1] 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,[2] and alters the expression of host and viral genes in combination with a neuron specific protein.[3][4] At later stages of cellular infection, ICP0 relocates to the cell cytoplasm to be incorporated into new virion particles.[5]

History and background

ICP0 was identified as an immediate-early polypeptide product of Herpes simplex virus-1 (HSV-1) infection in 1976.[6] 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.[7] This sequence predicted a 775 amino acid sequence with a molecular weight of 78.5 KDa.[7][8] 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

Dismantle microtubule networks

ICP0 co-localizes with α-tubulin, and dismantles host cell microtubule networks once it translocates to the cytoplasm.[9]

Transcription

In HSV-1 infected cells, ICP0 activates the transcription of many viral and cellular genes. It acts synergistically with HSV-1 immediate early (IE) protein, ICP4, and is essential for the reactivation of latent herpes virus and viral replication.[10]

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 the 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.[11][12] 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.[13] Barriers to viral replication induced by interferons can also be overcome by the action of ICP0.[14] This function of ICP0 also prevents the production of RNase L, an enzyme that degrades single-stranded viral and cellular RNAs and induces host cell apoptosis in virus infected cells.[15]

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.[16][17][18] HSV-1 ICP0 and several of its homologs in other herpes viruses bind to SUMO-1 in a manner similar to endogenous proteins,[19] causing depletion of SUMO-1, and disruption of nuclear bodies.[2][20][21][22][23][24]

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)[25][26] 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.[27] This interaction is attributed to the partial similarity of ICP0 to the human protein CoREST, also called REST corepressor 1 (RCOR1),[3] which combines with NRSF to repress expression of neuronal genes in non-neuronal cells.[27][28]

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.[29] 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.[4] The repressed production of immediate-early HSV genes may contribute to the establishment of latency during infection with herpes viruses.[4]

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.[4] Furthermore, an NRSF-binding region is located between the viral genes expressing proteins ICP4 and ICP22.[4] 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.[3][25]

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.[30] The RNA transcript is produced by the virus and accumulates in host cells during latent infection; it is known as Latency Associated Transcript (LAT).[30] 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.[31]

Silencing of ICP0 gene activity by ICP4

Although it is tempting to hypothesize that LAT is the repressor of the ICP0 gene, evidence supporting this hypothesis is lacking. Recent data suggest that ICP4 strongly suppresses the ICP0 gene, and ICP0 antagonizes ICP4.[32] The balance between ICP0 and ICP4 dictates whether the ICP0 gene can be efficiently transcribed.[32]

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.[33][34] 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).[35] 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.[36][37]

Herpes virus ICP-0 homologs and nomenclature
Herpes virusICP0 SynonymsStructural homology and functional similarity
HHV-1Herpes simplex virus-1 (HSV-1)ICP0, IE110(n/a)
HHV-2Herpes simplex virus-2 (HSV-2)has 61.5% amino acid sequence homology to HSV-1 ICP0.[34]
HHV-3Varicella zoster virus (VZV)ORF-61Shows homology to HSV-1 in the cysteine rich RING finger domain found at the N-terminal end of ORF-61. Two cell lines expressing VZV ORF-61 are specifically able to support infection by synthetic HSV with ICP0-deletion.[36]
SVVSimian varicella virusORF-61The mRNA for ORF-61 contains sequence that is antisense to SVV LAT, allowing for gene silencing of ORF-61 by SVV LAT in an analogous mechanism to ICP0 silencing by LAT in HSV-1.[35]
PRVPseudorabies virusEP0Both HSV-1 ICP0 and VZV ORF-61 support growth and infectability of PRV that is deficient in its ICP0 ortholog, EP0.[38]
HHV-4Epstein-Barr virus (EBV), lymphocryptovirusBZLF1Analogous to ICP0 and VZV ORF-61, BZLF1 is modified by SUMO-1 and disrupts PML Nuclear Bodies.[19]
HHV-5Cytomegalovirus (CMV)IE1, IE72[2]Disrupts PML bodies in a manner similar to ICP0.[23]

See also

References

  1. ↑ Edward K. Wagner. "Herpes simplex virus Research". Archived from the original on December 12, 2012. Retrieved Oct 25, 2007.
  2. 1 2 3 Lee HR, Kim DJ, Lee JM, et al. (June 2004). "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". J. Virol. 78 (12): 6527–42. doi:10.1128/JVI.78.12.6527-6542.2004. PMC 416510. PMID 15163746.
  3. 1 2 3 Gu H, Liang Y, Mandel G, Roizman B (May 2005). "Components of the REST/CoREST/histone deacetylase repressor complex are disrupted, modified, and translocated in HSV-1-infected cells". Proc. Natl. Acad. Sci. U.S.A. 102 (21): 7571–6. Bibcode:2005PNAS..102.7571G. doi:10.1073/pnas.0502658102. PMC 1140450. PMID 15897453.
  4. 1 2 3 4 5 Pinnoji RC, Bedadala GR, George B, Holland TC, Hill JM, Hsia SC (2007). "Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification". Virol. J. 4: 56. doi:10.1186/1743-422X-4-56. PMC 1906746. PMID 17555596.
  5. ↑ Sedlackova L, Rice SA (January 2008). "Herpes simplex virus type 1 immediate-early protein ICP27 is required for efficient incorporation of ICP0 and ICP4 into virions". Journal of Virology. 82 (1): 268–77. doi:10.1128/JVI.01588-07. PMC 2224399. PMID 17959681.
  6. ↑ Marsden HS, Crombie IK, Subak-Sharpe JH (June 1976). "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" (Free full-text). Journal of General Virology. 31 (3): 347–72. doi:10.1099/0022-1317-31-3-347. PMID 180249.
  7. 1 2 Perry LJ, Rixon FJ, Everett RD, Frame MC, McGeoch DJ (November 1986). "Characterization of the IE110 gene of herpes simplex virus type 1" (Free full-text). Journal of General Virology. 67 (11): 2365–80. doi:10.1099/0022-1317-67-11-2365. PMID 3023529.
  8. ↑ UniProt Consortium (24 July 2007). "Protein ICP0_HHV11". Retrieved 28 Oct 2007.
  9. ↑ Liu, Mingyu; William Halford (June 2010). "ICP0 Dismantles Microtubule Networks in Herpes Simplex Virus-Infected Cells". PLOS ONE. 5 (6): e10975. Bibcode:2010PLoSO...510975L. doi:10.1371/journal.pone.0010975. PMC 2882321. PMID 20544015.
  10. ↑ Everett RD (2000). "ICP0, a regulator of herpes simplex virus during lytic and latent infection". BioEssays. 22 (8): 761–70. doi:10.1002/1521-1878(200008)22:8<761::AID-BIES10>3.0.CO;2-A. PMID 10918307.
  11. ↑ Everett RD, Rechter S, Papior P, Tavalai N, Stamminger T, Orr A (2006). "PML contributes to a cellular mechanism of repression of herpes simplex virus type 1 infection that is inactivated by ICP0". J. Virol. 80 (16): 7995–8005. doi:10.1128/JVI.00734-06. PMC 1563828. PMID 16873256.
  12. ↑ Gu H, Roizman B (2003). "The degradation of promyelocytic leukemia and Sp100 proteins by herpes simplex virus 1 is mediated by the ubiquitin-conjugating enzyme UbcH5a". Proc. Natl. Acad. Sci. U.S.A. 100 (15): 8963–8. Bibcode:2003PNAS..100.8963G. doi:10.1073/pnas.1533420100. PMC 166421. PMID 12855769.
  13. ↑ Lin R, Noyce RS, Collins SE, Everett RD, Mossman KL (2004). "The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes". J. Virol. 78 (4): 1675–84. doi:10.1128/JVI.78.4.1675-1684.2004. PMC 369457. PMID 14747533.
  14. ↑ Mossman K (2005). "Analysis of anti-interferon properties of the herpes simplex virus type I ICP0 protein". Interferon Methods and Protocols. Vol. 116. pp. 195–205. doi:10.1385/1-59259-939-7:195. ISBN 978-1-58829-418-0. PMID 16000863. {{cite book}}: |journal= ignored (help)
  15. ↑ Sobol PT, Mossman KL (January 2006). "ICP0 prevents RNase L-independent rRNA cleavage in herpes simplex virus type 1-infected cells". J. Virol. 80 (1): 218–25. doi:10.1128/JVI.80.1.218-225.2006. PMC 1317541. PMID 16352546.
  16. ↑ Müller S, Matunis MJ, Dejean A (January 1998). "Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus". EMBO J. 17 (1): 61–70. doi:10.1093/emboj/17.1.61. PMC 1170358. PMID 9427741.
  17. ↑ Sternsdorf T, Jensen K, Will H (December 1997). "Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1". J. Cell Biol. 139 (7): 1621–34. doi:10.1083/jcb.139.7.1621. PMC 2132645. PMID 9412458.
  18. ↑ Kroetz MB (2005). "SUMO: a ubiquitin-like protein modifier". Yale J Biol Med. 78 (4): 197–201. PMC 2259148. PMID 16720014.
  19. 1 2 Adamson AL, Kenney S (March 2001). "Epstein-barr virus immediate-early protein BZLF1 is SUMO-1 modified and disrupts promyelocytic leukemia bodies". J. Virol. 75 (5): 2388–99. doi:10.1128/JVI.75.5.2388-2399.2001. PMC 114822. PMID 11160742.
  20. ↑ Xu Y, Ahn JH, Cheng M, et al. (November 2001). "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". J. Virol. 75 (22): 10683–95. doi:10.1128/JVI.75.22.10683-10695.2001. PMC 114650. PMID 11602710.
  21. ↑ Bailey D, O'Hare P (December 2002). "Herpes simplex virus 1 ICP0 co-localizes with a SUMO-specific protease". J. Gen. Virol. 83 (Pt 12): 2951–64. doi:10.1099/0022-1317-83-12-2951. PMID 12466471.
  22. ↑ Korioth F, Maul GG, Plachter B, Stamminger T, Frey J (November 1996). "The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1". Exp. Cell Res. 229 (1): 155–8. doi:10.1006/excr.1996.0353. PMID 8940259.
  23. 1 2 Müller S, Dejean A (June 1999). "Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption". J. Virol. 73 (6): 5137–43. doi:10.1128/JVI.73.6.5137-5143.1999. PMC 112559. PMID 10233977.
  24. ↑ Boutell C, Orr A, Everett RD (August 2003). "PML residue lysine 160 is required for the degradation of PML induced by herpes simplex virus type 1 regulatory protein ICP0". J. Virol. 77 (16): 8686–94. doi:10.1128/JVI.77.16.8686-8694.2003. PMC 167235. PMID 12885887.
  25. 1 2 Gu H, Roizman B (October 2007). "Herpes simplex virus-infected cell protein 0 blocks the silencing of viral DNA by dissociating histone deacetylases from the CoREST-REST complex". Proc. Natl. Acad. Sci. U.S.A. 104 (43): 17134–9. Bibcode:2007PNAS..10417134G. doi:10.1073/pnas.0707266104. PMC 2040395. PMID 17939992.
  26. ↑ Neuronal Restrictive Silencer Factor (NRSF) is also known as Repressor Element-1-Silencing Transcription factor (REST) and X2 Box Repressor (XBR): UniProt Consortium (11 September 2007). "Protein REST_HUMAN". Retrieved 28 Oct 2007.
  27. 1 2 Andrés ME, Burger C, Peral-Rubio MJ, et al. (August 1999). "CoREST: a functional corepressor required for regulation of neural-specific gene expression". Proc. Natl. Acad. Sci. U.S.A. 96 (17): 9873–8. Bibcode:1999PNAS...96.9873A. doi:10.1073/pnas.96.17.9873. PMC 22303. PMID 10449787.
  28. ↑ Mori N, Schoenherr C, Vandenbergh DJ, Anderson DJ (July 1992). "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". Neuron. 9 (1): 45–54. doi:10.1016/0896-6273(92)90219-4. PMID 1321646. S2CID 34561729.
  29. ↑ Shimojo M, Hersh LB (2004-03-19). "Regulation of the cholinergic gene locus by the repressor element-1 silencing transcription factor/neuron restrictive silencer factor (REST/NRSF)". Life Sci. 74 (18): 2213–25. doi:10.1016/j.lfs.2003.08.045. PMID 15017977.
  30. 1 2 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: Farrell MJ, Dobson AT, Feldman LT (February 1991). "Herpes simplex virus latency-associated transcript is a stable intron". Proc. Natl. Acad. Sci. U.S.A. 88 (3): 790–4. Bibcode:1991PNAS...88..790F. doi:10.1073/pnas.88.3.790. PMC 50899. PMID 1846963.
  31. ↑ Chen Q, Lin L, Smith S, Huang J, Berger SL, Zhou J (May 2007). "CTCF-dependent chromatin boundary element between the latency-associated transcript and ICP0 promoters in the herpes simplex virus type 1 genome". J. Virol. 81 (10): 5192–201. doi:10.1128/JVI.02447-06. PMC 1900208. PMID 17267480.
  32. 1 2 Liu, Mingyu; William Halford (January 2010). "ICP0 Antagonizes ICP4-Dependent Silencing of the Herpes Simplex Virus ICP0 Gene". PLOS ONE. 5 (1): e8837. Bibcode:2010PLoSO...5.8837L. doi:10.1371/journal.pone.0008837. PMC 2809113. PMID 20098619.
  33. ↑ UniProt Consortium (24 July 2007). "Protein ICP0_HHV2H". Retrieved 28 Oct 2007.
  34. 1 2 McGeoch DJ, Cunningham C, McIntyre G, Dolan A (December 1991). "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" (PDF). J. Gen. Virol. 72 (12): 3057–75. doi:10.1099/0022-1317-72-12-3057. PMID 1662697.
  35. 1 2 Ou Y, Davis KA, Traina-Dorge V, Gray WL (August 2007). "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 of Virology. 81 (15): 8149–56. doi:10.1128/JVI.00407-07. PMC 1951321. PMID 17507490.
  36. 1 2 Moriuchi H, Moriuchi M, Smith HA, Straus SE, Cohen JI (December 1992). "Varicella-zoster virus open reading frame 61 protein is functionally homologous to herpes simplex virus type 1 ICP0". Journal of Virology. 66 (12): 7303–8. doi:10.1128/JVI.66.12.7303-7308.1992. PMC 240434. PMID 1366099.
  37. ↑ Moriuchi H, Moriuchi M, Straus SE, Cohen JI (July 1993). "Varicella-zoster virus (VZV) open reading frame 61 protein transactivates VZV gene promoters and enhances the infectivity of VZV DNA". Journal of Virology. 67 (7): 4290–5. doi:10.1128/JVI.67.7.4290-4295.1993. PMC 237799. PMID 8389928.
  38. ↑ Moriuchi H, Moriuchi M, Dean H, Cheung AK, Cohen JI (May 1995). "Pseudorabies virus EPO is functionally homologous to varicella-zoster virus ORF61 protein and herpes simplex virus type 1 ICPO". Virology. 209 (1): 281–3. doi:10.1006/viro.1995.1256. PMID 7747481.
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