A herpesvirus ribosome-associated, RNA-binding protein confers a growth advantage upon mutants deficient in a GADD34-related function

The herpes simplex virus type 1 gamma 34.5 gene product and the cellular GA DD34 protein both contain similar domains that can regulate the activity of eukaryotic initiation factor 2 (eIF2), a critical translation initiation f actor. Viral mutants that lack the GADD34-related function grow poorly on a variety of malignant human cells, as activation of the cellular PKR kinase leads to the accumulation of inactive, phosphorylated eIF2 at late times p ostinfection. Termination of translation prior to the completion of the vir al reproductive cycle leads to impaired growth. Extragenic suppressors that regain the ability to synthesize proteins efficiently in the absence of th e viral GADD34-related function have been isolated. These suppressor allele s are dominant in trans and affect the steady-state accumulation of several viral mRNA species. We demonstrate that deregulated expression of Us11, a virus-encoded RNA-binding, ribosome-associated protein is necessary and suf ficient to confer a growth advantage upon viral mutants that lack a GADD34- related function. Ectopic expression of Us11 reduces the accumulation of th e activated cellular PKR kinase and allows for sustained protein synthesis. Thus, an RNA-binding, ribosome-associated protein (Us11) and a GADD34-rela ted protein (gamma 34.5) both function in a signal pathway that regulates t ranslation by modulating eIF2 phosphorylation.