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Journal of Virology, February 2009, p. 1260-1270, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01558-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Specific Inhibition of the PKR-Mediated Antiviral Response by the Murine Cytomegalovirus Proteins m142 and m143{triangledown}

Matthias Budt,1 Lars Niederstadt,1 Ralitsa S. Valchanova ,1,{dagger} Stipan Jonjic,2 and Wolfram Brune1*

Division of Viral Infections, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany,1 Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, Croatia2

Received 23 July 2008/ Accepted 12 November 2008

Double-stranded RNA (dsRNA) produced during viral infection activates several cellular antiviral responses. Among the best characterized is the shutoff of protein synthesis mediated by the dsRNA-dependent protein kinase (PKR) and the oligoadenylate synthetase (OAS)/RNase L system. As viral replication depends on protein synthesis, many viruses have evolved mechanisms for counteracting the PKR and OAS/RNase L pathways. The murine cytomegalovirus (MCMV) proteins m142 and m143 have been characterized as dsRNA binding proteins that inhibit PKR activation, phosphorylation of the translation initiation factor eIF2{alpha}, and a subsequent protein synthesis shutoff. In the present study we analyzed the contribution of the PKR- and the OAS-dependent pathways to the control of MCMV replication in the absence or presence of m142 and m143. We show that the induction of eIF2{alpha} phosphorylation during infection with an m142- and m143-deficient MCMV is specifically mediated by PKR, not by the related eIF2{alpha} kinases PERK or GCN2. PKR antagonists of vaccinia virus (E3L) or herpes simplex virus ({gamma}34.5) rescued the replication defect of an MCMV strain with deletions of both m142 and m143. Moreover, m142 and m143 bound to each other and interacted with PKR. By contrast, an activation of the OAS/RNase L pathway by MCMV was not detected in the presence or absence of m142 and m143, suggesting that these viral proteins have little or no influence on this pathway. Consistently, an m142- and m143-deficient MCMV strain replicated to high titers in fibroblasts lacking PKR but did not replicate in cells lacking RNase L. Hence, the PKR-mediated antiviral response is responsible for the essentiality of m142 and m143.

* Corresponding author. Mailing address: Division of Viral Infections, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany. Phone: 49 30 187542502. Fax: 49 30 18107542502. E-mail: BruneW{at}rki.de

{triangledown} Published ahead of print on 19 November 2008.

{dagger} Present address: Institute of Physiology, Charité-Universitätsmedizin Berlin, Arnimallee 22, 14195 Berlin, Germany.

Journal of Virology, February 2009, p. 1260-1270, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01558-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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