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Article: Tpl2/AP-1 enhances murine gammaherpesvirus 68 lytic replication

TitleTpl2/AP-1 enhances murine gammaherpesvirus 68 lytic replication
Authors
Issue Date2010
Citation
Journal of Virology, 2010, v. 84, n. 4, p. 1881-1890 How to Cite?
AbstractHow 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 γHV-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. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Persistent Identifierhttp://hdl.handle.net/10722/285661
ISSN
2023 Impact Factor: 4.0
2023 SCImago Journal Rankings: 1.378
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, Xudong-
dc.contributor.authorFeng, Jun-
dc.contributor.authorChen, Shijia-
dc.contributor.authorPeng, Li-
dc.contributor.authorHe, Wei Wu-
dc.contributor.authorQi, Jing-
dc.contributor.authorDeng, Hongyu-
dc.contributor.authorSun, Ren-
dc.date.accessioned2020-08-18T04:56:19Z-
dc.date.available2020-08-18T04:56:19Z-
dc.date.issued2010-
dc.identifier.citationJournal of Virology, 2010, v. 84, n. 4, p. 1881-1890-
dc.identifier.issn0022-538X-
dc.identifier.urihttp://hdl.handle.net/10722/285661-
dc.description.abstractHow 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 γHV-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. Copyright © 2010, American Society for Microbiology. All Rights Reserved.-
dc.languageeng-
dc.relation.ispartofJournal of Virology-
dc.titleTpl2/AP-1 enhances murine gammaherpesvirus 68 lytic replication-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1128/JVI.01856-09-
dc.identifier.pmid19939924-
dc.identifier.pmcidPMC2812393-
dc.identifier.scopuseid_2-s2.0-75449105004-
dc.identifier.volume84-
dc.identifier.issue4-
dc.identifier.spage1881-
dc.identifier.epage1890-
dc.identifier.isiWOS:000273853200023-
dc.identifier.issnl0022-538X-

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