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Journal of Virology, February 2010, p. 1881-1890, Vol. 84, No. 4
0022-538X/10/$012.00+0     doi:10.1128/JVI.01856-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Tpl2/AP-1 Enhances Murine Gammaherpesvirus 68 Lytic Replication{triangledown}

Xudong Li,1 Jun Feng,1 Shijia Chen,1 Li Peng,1 Wei-Wu He,2 Jing Qi,4 Hongyu Deng,3,4 and Ren Sun1*

Department of Molecular and Medical Pharmacology, UCLA David Geffen School of Medicine, Los Angeles, California 90095,1 OriGene Technologies Inc., Six Taft Court, Suite 100, Rockville, Maryland 20850,2 School of Dentistry, UCLA, Los Angeles, California 90095,3 Institute of Biophysics, Chinese Academy of Sciences, Beijing, People's Republic of China4

Received 2 September 2009/ Accepted 16 November 2009

How cellular factors regulate gammaherpesvirus lytic replication is not well understood. Here, through functional screening of a cellular kinase expression library, we identified mitogen-activated protein kinase kinase kinase 8 (MAP3K8/Tpl2) as a positive regulator of murine gammaherpesvirus 68 (MHV-68 or {gamma}HV-68) lytic gene expression and replication. Tpl2 enhances MHV-68 lytic replication by upregulating lytic gene expression and promoter activities of viral lytic genes, including RTA and open reading frame 57 (ORF57). By screening a cellular transcription factor library, we identified the Fos AP-1 transcription factor as a downstream factor that is both necessary and sufficient for mediating the enhancement of MHV-68 lytic replication by Tpl2. In addition, Tpl2 stimulates the promoter activities of key viral lytic genes, including RTA and ORF57, in an AP-1-dependent manner. We identified an AP-1-responsive element on the MHV-68 RTA promoter as the cis element mediating the upregulation of RTA promoter activity by Tpl2. MHV-68 lytic infection upregulates Fos expression, AP-1 activity, and RTA promoter activity in a Tpl2-dependent manner. We constructed a mutant MHV-68 virus that abolished this AP-1-responsive element. This mutant virus exhibited attenuated lytic replication kinetics, indicative of a critical role of this AP-1-responsive element during lytic replication. Moreover, Tpl2 knockdown inhibited the lytic replication of wild-type MHV-68 (MHV-68-WT) but not that of the MHV-68 mutant virus, indicating that endogenous Tpl2 promotes efficient virus lytic replication through AP-1-dependent upregulation of RTA expression. In summary, through tandem functional screens, we identified the Tpl2/AP-1 signaling transduction pathway as a positive regulator of MHV-68 lytic replication.

* Corresponding author. Mailing address: CHS23-120, 10833 Le Conte Avenue, Los Angeles, CA 90095. Phone: (310) 794-5557. Fax: (310) 794-5123. E-mail: rsun{at}mednet.ucla.edu

{triangledown} Published ahead of print on 25 November 2009.

Journal of Virology, February 2010, p. 1881-1890, Vol. 84, No. 4
0022-538X/10/$012.00+0     doi:10.1128/JVI.01856-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.





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