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Journal of Virology, May 2006, p. 4422-4430, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4422-4430.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Negative Regulation of the Alpha Interferon-Induced Antiviral Response by the Ras/Raf/MEK Pathway

Sarah M. Battcock, Thaddeus W. Collier, Dong Zu, and Kensuke Hirasawa^*

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

Received 6 October 2005/ Accepted 9 February 2006

Interferon (IFN) is one of the molecules released by virus-infected cells, resulting in the establishment of an antiviral state within infected and neighboring cells. IFN-induced antiviral response may be subject to modulation by the cellular signaling environment of host cells which impact the effectiveness of viral replication. Here, we show that cells with an activated Ras/Raf/MEK signaling cascade allow propagation of viruses in the presence of IFN. Ras-transformed (RasV12) and vector control NIH 3T3 cells were infected with vesicular stomatitis virus (VSV) or an IFN-sensitive vaccinia virus (delE3L) in the presence of alpha interferon. While IFN protected vector control cells from infection by both viruses, RasV12 cells were susceptible to viral infection regardless of the presence of IFN. IFN sensitivity was restored in RasV12 cells upon RNA interference (RNAi) knockdown of Ras. We further investigated which elements downstream of Ras are responsible for counteracting IFN-induced antiviral responses. A Ras effector domain mutant that can only stimulate the Raf kinase family of effectors was able to suppress the IFN response and allow VSV replication. IFN-induced antiviral mechanisms were also restored in RasV12 cells by treatment with a MEK inhibitor (U0126 or PD98059). Moreover, by using RNAi to MEK1 and MEK2, we determined that MEK2, rather than MEK1, is responsible for suppression of the IFN response. In conclusion, our results suggest that activation of the Ras/Raf/MEK pathway downregulates IFN-induced antiviral response.

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* Corresponding author. Mailing address: Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, Rm. 1810, 300 Prince Philip Dr., St. John's A1B3V6, Canada. Phone: (709) 777-8291. Fax: (709) 777-8294. E-mail: kensuke{at}mun.ca.

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Journal of Virology, May 2006, p. 4422-4430, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4422-4430.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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