Selective degradation of mRNAs by the HSV host shutoff RNase is regulated by the UL47 tegument protein

Herpes simplex virus 1 (HSV-1) encodes an endoribonuclease that is responsible for the shutoff of host protein synthesis [virion host shutoff (VHS)-RNase]. The VHS-RNase released into cells during infection targets differentially four classes of mRNAs. Thus, (a) VHS-RNase degrades stable cellular mRNAs and alpha (immediate early) viral mRNAs; (b) it stabilizes host stress response mRNAs after deadenylation and subsequent cleavage near the adenylate-uridylate (AU)-rich elements; (c) it does not effectively degrade viral beta or gamma mRNAs; and (d) it selectively spares from degradation a small number of cellular mRNAs. Current evidence suggests that several viral and at least one host protein (tristetraprolin) regulate its activity. Thus, virion protein (VP) 16 and VP22 neutralize the RNase activity at late times after infection. By binding to AU-rich elements via its interaction with tristetraprolin, the RNase deadenylates and cleaves the mRNAs in proximity to the AU-rich elements. In this report we show that another virion protein, U(L)47, brought into the cell during infection, attenuates the VHS-RNase activity with respect to stable host and viral alpha mRNAs and effectively blocks the degradation of beta and gamma mRNAs, but it has no effect on the processing of AU-rich mRNAs. The properties of U(L)47 suggest that it, along with the alpha protein infected cell protein 27, attenuates degradation of mRNAs by the VHS-RNase through interaction with the enzyme in polyribosomes. Mutants lacking both VHS-RNase and U(L)47 overexpress a genes and delay the expression of beta and gamma genes, suggesting that overexpression of a genes inhibits the downstream expression of early and late genes.