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Journal of Virology, July 2009, p. 6717-6726, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02213-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Activated Ras/MEK Inhibits the Antiviral Response of Alpha Interferon by Reducing STAT2 Levels{triangledown} ,{dagger}

Sherri L. Christian, Thaddeus W. Collier, Dong Zu, Maria Licursi, Chris M. Hough, and Kensuke Hirasawa*

Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada

Received 20 October 2008/ Accepted 14 April 2009

The ability of interferon (IFN) to induce the expression of antiviral genes, and therefore suppress viral infection, is dependent on the activity of cellular suppressors. The Ras/MEK pathway is one of these cellular suppressors, since the activation of Ras/MEK permits viral replication in the presence of alpha IFN (IFN-{alpha}). Here, we have investigated the mechanism by which activated Ras/MEK inhibits the IFN-{alpha} response. We found that the induction of antiviral proteins in response to IFN-{alpha} was impaired in Ras-transformed NIH 3T3 (RasV12) cells. The inhibition of the Ras/MEK pathway restored the IFN-mediated induction of antiviral genes, indicating that activated Ras interrupts the IFN pathway upstream of antiviral gene transcription. Indeed, the IFN-induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 was inhibited in RasV12 cells compared to that of vector control cells. In addition, we found that the total amount of STAT2 was reduced in RasV12 cells. To determine if the impaired IFN-{alpha} response can be rescued by restoring the overall level of STAT2, we overexpressed STAT2 in RasV12 cells. The IFN-{alpha}-induced phosphorylation of STAT1 and STAT2, as well as the expression of antiviral protein, were restored, and IFN-induced antiviral protection was partially restored. Moreover, we demonstrated that the downregulation of STAT2 levels by Ras/MEK was mediated at the transcriptional level. Thus, the activation of the Ras/MEK pathway reduces the amount of STAT2 available for propagating the IFN signal, resulting in the impairment of the IFN-{alpha}-induced antiviral response.

* Corresponding author. Mailing address: Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Dr., St. John's, Newfoundland A1B3V6, Canada. Phone: (709) 777-8291. Fax: (709) 777-8294. E-mail: kensuke{at}mun.ca

{triangledown} Published ahead of print on 22 April 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, July 2009, p. 6717-6726, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02213-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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