Functional Anatomy of Herpes Simplex Virus 1 Overlapping Genes Encoding Infected-Cell Protein 22 and U S 1.5 Protein

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Abstract
Earlier studies have shown that (i) the coding domain of the α22 gene encodes two proteins, the 420-amino-acid infected-cell protein 22 (ICP22) and a protein, U S 1.5, which is initiated from methionine 147 of ICP22 and which is colinear with the remaining portion of that protein; (ii) posttranslational processing of ICP22 mediated largely by the viral protein kinase U L 13 yields several isoforms differing in electrophoretic mobility; and (iii) mutants lacking the carboxyl-terminal half of the ICP22 and therefore ΔU S 1.5 are avirulent and fail to express normal levels of subsets of both α (e.g., ICP0) or γ 2 (e.g., U S 11 and U L 38) proteins. We have generated and analyzed two sets of recombinant viruses. The first lacked portions of or all of the sequences expressed solely by ICP22. The second set lacked 10 to 40 3′-terminal codons of ICP22 and U S 1.5. The results were as follows. (i) In cells infected with mutants lacking amino-terminal sequences, translation initiation begins at methionine 147. The resulting protein cannot be differentiated in mobility from authentic U S 1.5, and its posttranslational processing is mediated by the U L 13 protein kinase. (ii) Expression of U S 11 and U L 38 genes by mutants carrying only the U S 1.5 gene is similar to that of wild-type parent virus. (iii) Mutants which express only U S 1.5 protein are avirulent in mice. (iv) The coding sequences Met147 to Met171 are essential for posttranslational processing of the U S 1.5 protein. (v) ICP22 made by mutants lacking 15 or fewer of the 3′-terminal codons are posttranslationally processed whereas those lacking 18 or more codons are not processed. (vi) Wild-type and mutant ICP22 proteins localized in both nucleus and cytoplasm irrespective of posttranslational processing. We conclude that ICP22 encodes two sets of functions, one in the amino terminus unique to ICP22 and one shared by ICP22 and U S 1.5. These functions are required for viral replication in experimental animals. U S 1.5 protein must be posttranslationally modified by the U L 13 protein kinase to enable expression of a subset of late genes exemplified by U L 38 and U S 11. Posttranslational processing is determined by two sets of sequences, at the amino terminus and at the carboxyl terminus of U S 1.5, respectively, a finding consistent with the hypothesis that both domains interact with protein partners for specific functions.

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