The 775 residue infected cell protein No.O (ICPO) of herpes simplex virus 1 (HSV-1) is a multifunctional protein known primarily as a promiscuous transactivator. Studies initiated during the previous grant period demonstrated that it contains ubiquitin ligase sites mapping in exon 2 (residues 20- to 241) and near the carboxyl terminal of exon 3 (residues 600 to 775). The objective of the studies done during the current period were to (a) define the role of ICPO as an unbiquitin ligase, (b) investigate the role of ICPO during early stages of infection, and, (c) identify the functions encoded in the uncharted domains (residues 242-500) of ICPO. We have accomplished the following: (i) We have demonstrated that one of the ICPO ubiquitin ligase activities targets PML. By specifically degrading PML, HSV blocks exogenous interferon from activating antiviral responses, (ii)We have demonstrated for the first time that the role of ICPO is similar to that of histone deacetylase (HDAC) inhibitors. ICPO interacts with the represser complex CoREST/REST/HDAC1-2 to dislodge HDAC1-2 from this complex. In essence, on release of viral DNA from virions into the nucleus, it is confronted by numerous cellular proteins whose function it is to either express of shutoff viral DNA. HSV encodes three proteins, ccTIF (VP16) which is brought into the nucleus to enable the expression of a genes, ICPO, which blocks the silencing of all downstream genes, and US3 protein kinase (recently shown to phopshorylate HDAC1-2) to enable gene expression in transduced cells. All DNA viruses have a similar problem - howto block silencing, of its genes by cellular repressers. We have demonstrated that the problem is real and that viruses have found a way to solve this problem, (iii) The cell surface is a giant antenna that radiates signals to the environment and also conveys signals from the environment to the cell. Studies of previously uncharted domain of ICPO led to the discovery of motifs for binding SH3 domains. This led to a fundamental discovery that the virus targets surface receptors in many different ways. CIN85 and Cbl are blocked from cycling to the cell surface. TNFa receptor disappears because the protein is short lived and the virus degrades its mRNA. Interferon y receptor appears to be phosphorylated by a viral protein kinase and studies are in progress to determine whether this results in inactivation of the receptor. Our objective in the next grant interval are to (i) define role of ICPO in blocking the attempt by the host cell to silence the expression of viral genes, (ii)define the role of anti silencing activity of ICPO in establishment of latency, reactivation, and pathogenicity and (iii) define the consequences of the interaction of ICPO with SH3 domain proteins. The studies on ICPO are central to an understanding of the mechanisms by which viruses thwart fundamental mechanisms of cellular defences to infection.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Daschner, Phillip J
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University of Chicago
Schools of Medicine
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Du, Te; Zhou, Guoying; Roizman, Bernard (2013) Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3. Proc Natl Acad Sci U S A 110:E2621-8
Gu, Haidong; Zheng, Yi; Roizman, Bernard (2013) Interaction of herpes simplex virus ICP0 with ND10 bodies: a sequential process of adhesion, fusion, and retention. J Virol 87:10244-54
Roizman, Bernard; Whitley, Richard J (2013) An inquiry into the molecular basis of HSV latency and reactivation. Annu Rev Microbiol 67:355-74
Zhou, Guoying; Du, Te; Roizman, Bernard (2013) The role of the CoREST/REST repressor complex in herpes simplex virus 1 productive infection and in latency. Viruses 5:1208-18
Zhou, Guoying; Du, Te; Roizman, Bernard (2013) HSV carrying WT REST establishes latency but reactivates only if the synthesis of REST is suppressed. Proc Natl Acad Sci U S A 110:E498-506
Kalamvoki, Maria; Gu, Haidong; Roizman, Bernard (2012) Overexpression of the ubiquitin-specific protease 7 resulting from transfection or mutations in the ICP0 binding site accelerates rather than depresses herpes simplex virus 1 gene expression. J Virol 86:12871-8
Du, Te; Zhou, Guoying; Roizman, Bernard (2012) Induction of apoptosis accelerates reactivation of latent HSV-1 in ganglionic organ cultures and replication in cell cultures. Proc Natl Acad Sci U S A 109:14616-21
Mallon, Stephen; Wakim, Bassam T; Roizman, Bernard (2012) Use of biotinylated plasmid DNA as a surrogate for HSV DNA to identify proteins that repress or activate viral gene expression. Proc Natl Acad Sci U S A 109:E3549-57
Roizman, Bernard (2011) The checkpoints of viral gene expression in productive and latent infection: the role of the HDAC/CoREST/LSD1/REST repressor complex. J Virol 85:7474-82
Roizman, Bernard; Zhou, Guoying; Du, Te (2011) Checkpoints in productive and latent infections with herpes simplex virus 1: conceptualization of the issues. J Neurovirol 17:512-7

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