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Resistance of mRNA Translation to Acute Endoplasmic Reticulum Stress-Inducing Agents in Herpes Simplex Virus Type 1-Infected Cells Requires Multiple Virus-Encoded Functions

Department of Microbiology, New York University School of Medicine, and NYU Cancer Institute, New York, New York 10016

Received 7 March 2006/ Accepted 15 May 2006

Via careful control of multiple kinases that inactivate the critical translation initiation factor eIF2 by phosphorylation of its alpha subunit, the cellular translation machinery can rapidly respond to a spectrum of environmental stresses, including viral infection. Indeed, virus replication produces a battery of stresses, such as endoplasmic reticulum (ER) stress resulting from misfolded proteins accumulating within the lumen of this organelle, which could potentially result in eIF2 phosphorylation and inhibit translation. While cellular translation is exquisitely sensitive to ER stress-inducing agents, protein synthesis in herpes simplex virus type 1 (HSV-1)-infected cells is notably resistant. Sustained translation in HSV-1-infected cells exposed to acute ER stress does not involve the interferon-induced, double-stranded RNA-responsive eIF2 kinase PKR, and it does not require either the PKR inhibitor encoded by the Us11 gene or the eIF2 phosphatase component specified by the ₁34.5 gene, the two viral functions known to regulate eIF2 phosphorylation. In addition, although ER stress potently induced the GADD34 cellular eIF2 phosphatase subunit in uninfected cells, it did not accumulate to detectable levels in HSV-1-infected cells under identical exposure conditions. Significantly, resistance of translation to the acute ER stress observed in infected cells requires HSV-1 gene expression. Whereas blocking entry into the true late phase of the viral developmental program does not abrogate ER stress-resistant translation, the presence of viral immediate-early proteins is sufficient to establish a state permissive of continued polypeptide synthesis in the presence of ER stress-inducing agents. Thus, one or more previously uncharacterized viral functions exist to counteract the accumulation of phosphorylated eIF2 in response to ER stress in HSV-1-infected cells.

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