The alpha22 gene of herpes simplex virus 1 encodes two mRNAs. These direct the synthesis of the 420 amino acid infected cell protein No. 22 (ICP22) and the US 1.5 protein initiated at the ICP22 met147. To facilitate discussion, we define the ICP22 domain as unique to that protein and the US1.5 domain as that shared by the two proteins. Both domains are essential for viral replication in experimental animals but not in HEp-2 or Vero (permissive) cells. The US1.5 domain is necessary for optimal replication in primary human cell cultures and rodent (restrictive) cells. The US1.5 domain is phosphorylated by the UL13 protein kinase,- a requirement for viral replication in experimental animals or for optimal replication in restrictive cells. The ICP22 domain is nucleotidylylated and binds cell cycle-dependent protein p78. A host protein, p60, binds unprocessed US1.5 protein and ICP0. In permissive cells, p60 is translocated to small nuclear bodies with ICP0 even in the absence of US1.5 protein whereas in restrictive cells p60 is posttranslationally processed by ICP22/US1.5 and UL13 proteins but is not translocated. The objectives of this proposal are to (i) define the sequences and separate the functional domains of ICP22 and of US1.5 protein. The fundamental hypothesis is that ICP22/US1.5 gene complex expresses several functions which may be separable into different genes. If true, it would facilitate further studies of their functions; (ii) determine the function of p60 in relation to viral replication in permissive and restrictive cells. The fundamental hypothesis is that p60 must be sequestered in the small nuclear bodies by ICP0 (permissive cells) or posttranslationally modified by ICP22/US1.5 and UL13 proteins (restrictive cells) for optimal replication; (iii) map the site(s) of posttranslational modifications of ICP22 and US1.5 protein. Mutants lacking UL13 exhibit a phenotype similar to that of mutants lacking US1.5 sequences. Is UL13 required solely to phosphorylate US1.5 or does it act independently? (iv) map and define the functions of the ICP22 domain. The hypothesis is that the functions of ICP22 domain are different from those of the US1.5 domain.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA083939-01
Application #
6031207
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Daschner, Phillip J
Project Start
2000-01-01
Project End
2004-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
1
Fiscal Year
2000
Total Cost
$440,321
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Jovasevic, Vladimir; Liang, Li; Roizman, Bernard (2008) Proteolytic cleavage of VP1-2 is required for release of herpes simplex virus 1 DNA into the nucleus. J Virol 82:3311-9
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
Smith-Donald, Benjamin A; Roizman, Bernard (2008) The interaction of herpes simplex virus 1 regulatory protein ICP22 with the cdc25C phosphatase is enabled in vitro by viral protein kinases US3 and UL13. J Virol 82:4533-43
Durand, Lizette Olga; Roizman, Bernard (2008) Role of cdk9 in the optimization of expression of the genes regulated by ICP22 of herpes simplex virus 1. J Virol 82:10591-9
Zhou, Guoying; Roizman, Bernard (2007) Separation of receptor-binding and profusogenic domains of glycoprotein D of herpes simplex virus 1 into distinct interacting proteins. Proc Natl Acad Sci U S A 104:4142-6
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

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