Herpes simplex viruses (HSV) package and bring into cells an
RNase designated virion host shutoff (VHS)
RNase. In infected cells, the VHS
RNase targets primarily stress response mRNAs characterized by the presence of AU-rich elements in their
3' untranslated regions (
UTRs). In uninfected cells, these RNAs are sequestered in exosomes or P bodies by host
proteins that bind to the AU-rich elements. In infected cells, the AU-rich RNAs are deadenylated and cleaved close to the AU-rich elements, leading to long-term persistence of nontranslatable RNAs consisting of the 5' portions of the cleavage products. The host
proteins that bind to the AU-rich elements are either resident in cells (e.g., TIA-1) or induced (e.g.,
tristetraprolin). Earlier, this laboratory reported that
tristetraprolin binds VHS
RNase. To test the hypothesis that
tristetraprolin directs VHS
RNase to the AU-rich elements, we mapped the domains of VHS and
tristetraprolin required for their interactions. We report that VHS binds to the domain of
tristetraprolin that enables its interaction with
RNA. A single amino acid substitution in that domain abolished the interaction with
RNA but did not block the binding to VHS
RNase. In transfected cells, the mutant but not the wild-type
tristetraprolin precluded the degradation of the AU-rich RNAs by VHS
RNase. We conclude that
TTP mediates the cleavage of the
3' UTRs of stress response mRNAs by recruiting the VHS
RNase to the AU-rich elements.
IMPORTANCE: The primary host response to HSV
infection is the synthesis of stress response mRNAs characterized by the presence of AU-rich elements in their
3' UTRs. These mRNAs are the targets of the virion host shutoff (VHS)
RNase. The VHS
RNase binds both to
mRNA cap structure and to
tristetraprolin, an inducible host
protein that sequesters AU-rich mRNAs in exosomes or P bodies. Here we show that
tristetraprolin recruits VHS
RNase to the AU-rich elements and enables the degradation of the stress response mRNAs.