The Herpes Simplex Virus Type 1 U S 11 Protein Interacts with Protein Kinase R in Infected Cells and Requires a 30-Amino-Acid Sequence Adjacent to a Kinase Substrate Domain

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Abstract
The herpes simplex virus type 1 γ 1 34.5 gene product precludes the host-mediated protein shutoff response induced by activated protein kinase R (PKR). Earlier studies demonstrated that recombinant viruses lacking the γ 1 34.5 gene (Δγ 1 34.5) developed secondary mutations that allowed earlier U S 11 expression and enabled continued protein synthesis. Further, in vitro studies demonstrated that a recombinant expressed U S 11 protein binds PKR, blocks the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF-2α) by activated PKR, and, if provided prior to PKR activation, precluded PKR autophosphorylation. The present study furthers the hypothesis that early U S 11 production precludes PKR-mediated host protein shutoff by demonstrating that (i) U S 11 and PKR interact in the context of viral infection, (ii) this interaction is RNA dependent and requires a 30-amino-acid domain (amino acids 91 to 121) in the carboxyl domain of the U S 11 protein, (iii) the proteins biochemically colocalize in the S100 ribosomal fraction, and (iv) there is a PKR substrate domain immediately adjacent to the binding domain. The results suggest that the U S 11 interaction with PKR at the ribosome is RNA dependent and that the U S 11 protein contains a substrate domain with homology to eIF-2α in close proximity to an essential binding domain.

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