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Journal of Virology, March 2009, p. 2510-2517, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02416-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mitogen-Activated Protein Kinase-Activated Kinase RSK2 Plays a Role in Innate Immune Responses to Influenza Virus Infection{triangledown}

Satoshi Kakugawa,1 Masayuki Shimojima,1 Hideo Goto,1 Taisuke Horimoto,1 Naoki Oshimori,3 Gabriele Neumann,5 Tadashi Yamamoto,3 and Yoshihiro Kawaoka1,2,4,5*

Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,1 Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency, Saitama 332-0012, Japan,2 Division of Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,3 International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan,4 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 537065

Received 24 November 2008/ Accepted 29 December 2008

Viral infections induce signaling pathways in mammalian cells that stimulate innate immune responses and affect cellular processes, such as apoptosis, mitosis, and differentiation. Here, we report that the ribosomal protein S6 kinase alpha 3 (RSK2), which is activated through the "classical" mitogen-activated protein kinase pathway, plays a role in innate immune responses to influenza virus infection. RSK2 functions in the regulation of cell growth and differentiation but was not known to play a role in the cellular antiviral response. We have found that knockdown of RSK2 enhanced viral polymerase activity and growth of influenza viruses. Influenza virus infection stimulates NK-{kappa}B- and beta interferon-dependent promoters. This stimulation was reduced in RSK2 knockdown cells, suggesting that RSK2 executes its effect through innate immune response pathways. Furthermore, RSK2 knockdown suppressed influenza virus-induced phosphorylation of the double-stranded RNA-activated protein kinase PKR, a known antiviral protein. These findings establish a role for RSK2 in the cellular antiviral response.

* Corresponding author. Mailing address: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5310. Fax: 81-3-5449-5408. E-mail: kawaoka{at}ims.u-tokyo.ac.jp

{triangledown} Published ahead of print on 7 January 2009.

Journal of Virology, March 2009, p. 2510-2517, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02416-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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