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J. Biol. Chem., Vol. 280, Issue 14, 13512-13519, April 8, 2005

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Inhibition of Host and Viral Translation during Vesicular Stomatitis Virus Infection

eIF2 IS RESPONSIBLE FOR THE INHIBITION OF VIRAL BUT NOT HOST TRANSLATION^*

John H. Connor and Douglas S. Lyles

From the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

In cells that allow replication of vesicular stomatitis virus (VSV), there are two phases of translation inhibition: an early block of host translation and a later inhibition of viral translation. We investigated the phosphorylation of the subunit of the eIF2 complex during these two phases of viral infection. In VSV-infected cells, the accumulation of phosphorylated (inactivated) eIF2 did not begin until well after host protein synthesis was inhibited, suggesting that it only plays a role in blocking viral translation later after infection. Consistent with this, cells expressing an unphosphorylatable eIF2 showed prolonged viral protein synthesis without an effect on host protein synthesis inhibition. Induction of eIF2 phosphorylation at early times of viral infection by treatment with thapsigargin showed that virus and host translation are similarly inhibited, demonstrating that viral and host messages are similarly sensitive to eIF2 phosphorylation. A recombinant virus that expresses a mutant matrix protein and is defective in the inhibition of host and virus protein synthesis showed an altered phosphorylation of eIF2, demonstrating an involvement of viral protein function in inducing this antiviral response. This analysis of eIF2 phosphorylation, coupled with earlier findings that the eIF4F complex is modified earlier during VSV infection, supports a temporal/kinetic model of translation control, where at times soon after infection, changes in the eIF4F complex result in the inhibition of host protein synthesis; at later times, inactivation of the eIF2 complex blocks VSV protein synthesis.

Received for publication, February 1, 2005

^* This work was supported by Public Service Health Service Grants AI052304 and AI32983 from the National Institute of Allergy and Infectious Diseases, NIH (to D.S.L). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Signal Transduction Mechanisms and Cell Function training program grant CA09422 from NCI and Public Health Service Grant AI051805 from the National Institute of Allergy and Infectious Diseases, NIH. To whom correspondence should be addressed: Tel.: 336-716-2270; Fax: 336-716-9928; E-mail: jconnor{at}wfubmc.edu.

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