Tpl2/AP-1 enhances murine gammaherpesvirus 68 lytic replication.

Abstract

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 gammaHV-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.

• Authors: Xudong Li, Jun Feng, Shijia Chen, Li Peng, Wei-Wu He, Jing Qi, Hongyu Deng, Ren Sun
• Journal: Journal of virology (J Virol) Vol. 84 Issue 4 Pg. 1881-90 (Feb 2010) ISSN: 1098-5514 [Electronic] United States
• PMID: 19939924 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Viral
• Immediate-Early Proteins
• Proto-Oncogene Proteins
• Recombinant Proteins
• Trans-Activators
• Transcription Factor AP-1
• MAP Kinase Kinase Kinases
• MAP3K8 protein, human

Topics

• Animals
• Base Sequence
• Cell Line
• Chlorocebus aethiops
• Cricetinae
• DNA, Viral (genetics)
• Genes, Viral
• Host-Pathogen Interactions (genetics, physiology)
• Humans
• Immediate-Early Proteins (genetics, physiology)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, genetics, physiology)
• Mice
• Models, Biological
• Promoter Regions, Genetic
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics, physiology)
• Recombinant Proteins (genetics, metabolism)
• Rhadinovirus (genetics, physiology)
• Signal Transduction
• Trans-Activators (genetics, physiology)
• Transcription Factor AP-1 (physiology)
• Vero Cells
• Virus Replication (genetics, physiology)