The infected cell protein No.0 (ICP0) is the product of the alpha-0 genes herpes simplex viruses 1 and 2. The gene is expressed immediately after infection and it functions as an important promiscuous transactivator induced into cells by infection or transfection. While it merely enhances viral replication in dividing cells, alpha-0 is essential for productive infection in experimental animal systems, in non dividing cells, for the establishment of latency and for reactivation. The chief characteristics of ICP0 that form the basis of ongoing and proposed studies are as follows: (i) The gene contains two introns. Intron 1, the largest, contains 1 splice donor and 4 splice acceptor sites. RNAs extracted from infected cells form 4 populations predicted to make a family of proteins. (ii) Intron I RNA is nonpolyadenylated, transported into the cytoplasm and is more stable than the ICP0 mRNA. (iii) The 775-amino acid protein contains a zinc finger and a nuclear localization and a nucleotidylation signal sequence; it is also phosphorylated by the viral kinase. ICP0 has been shown to bind in a meaningful fashion to a ubiquitin-specific protease, to the translation elongation factor EF-1-delta and to bind and stabilize cyclin D3. Additional cellular proteins which appear to bind to ICP0 have been identified. These data indicate that ICP0 is an important multifunctional protein and suggest that the perceived function as a potent promiscuous transactivator reflects the sum total of the interactions of the protein and of the stable intron RNA with cellular and viral proteins. The proposed studies are to determine (i) the function of intron I of ICP0: verification of the existence of alternately spliced mRNAs and products of these mRNAs; (ii) the function of Intron I mRNA, (iii) the functions expressed by uncharted domains of ICP0; and (iv) the role of the ICP0 ligands in the biology of the viral infection. The experimental design involves identification of interactive ligands, identification of minimal ICP0 domains that interact with these ligands, and construction of recombinant viruses whose ICP0 will no longer interact with these ligands. The experimental design includes identification of the products of alternative splicing and characterization of the role of the ligands in infection.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Virology Study Section (EVR)
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Wong, May
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University of Chicago
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Roizman, Bernard; Zhou, Guoying (2015) The 3 facets of regulation of herpes simplex virus gene expression: A critical inquiry. Virology 479-480:562-7
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
Gu, Haidong; Roizman, Bernard (2009) The two functions of herpes simplex virus 1 ICP0, inhibition of silencing by the CoREST/REST/HDAC complex and degradation of PML, are executed in tandem. J Virol 83:181-7
Smith-Donald, Benjamin A; Durand, Lizette O; Roizman, Bernard (2008) Role of cellular phosphatase cdc25C in herpes simplex virus 1 replication. J Virol 82:4527-32
Kalamvoki, Maria; Qu, Jianguo; Roizman, Bernard (2008) Translocation and colocalization of ICP4 and ICP0 in cells infected with herpes simplex virus 1 mutants lacking glycoprotein E, glycoprotein I, or the virion host shutoff product of the UL41 gene. J Virol 82:1701-13
Taddeo, Brunella; Sciortino, Maria Teresa; Zhang, Weiran et al. (2007) Interaction of herpes simplex virus RNase with VP16 and VP22 is required for the accumulation of the protein but not for accumulation of mRNA. Proc Natl Acad Sci U S A 104:12163-8
Poon, Alice P W; Roizman, Bernard (2007) Mapping of key functions of the herpes simplex virus 1 U(S)3 protein kinase: the U(S)3 protein can form functional heteromultimeric structures derived from overlapping truncated polypeptides. J Virol 81:1980-9
Kalamvoki, Maria; Roizman, Bernard (2007) Bcl-2 blocks accretion or depletion of stored calcium but has no effect on the redistribution of IP3 receptor I mediated by glycoprotein E of herpes simplex virus 1. J Virol 81:6316-25
Sciortino, Maria Teresa; Taddeo, Brunella; Giuffre-Cuculletto, Maria et al. (2007) Replication-competent herpes simplex virus 1 isolates selected from cells transfected with a bacterial artificial chromosome DNA lacking only the UL49 gene vary with respect to the defect in the UL41 gene encoding host shutoff RNase. J Virol 81:10924-32
Gu, Haidong; Roizman, Bernard (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 104:17134-9

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