Tpl2/AP-1 enhances murine gammaherpesvirus 68 lytic replication

Area of Science:

• Virology
• Molecular Biology
• Cellular Signaling

Background:

• Cellular factors regulating gammaherpesvirus lytic replication remain poorly understood.
• Murine gammaherpesvirus 68 (MHV-68) serves as a model for studying gammaherpesvirus replication dynamics.

Purpose of the Study:

• To identify cellular factors that regulate MHV-68 lytic replication.
• To elucidate the molecular mechanisms by which identified factors influence viral gene expression and replication.

Main Methods:

• Functional screening of cellular kinase and transcription factor libraries.
• Analysis of viral gene expression and promoter activity (RTA, ORF57).
• Construction and characterization of a mutant MHV-68 virus with an abolished AP-1-responsive element.

Main Results:

• Mitogen-activated protein kinase kinase kinase 8 (MAP3K8/Tpl2) was identified as a positive regulator of MHV-68 lytic replication.
• The Fos AP-1 transcription factor mediates Tpl2's enhancement of MHV-68 replication by upregulating viral lytic gene promoters.
• A mutant MHV-68 virus lacking the AP-1-responsive element on the RTA promoter showed attenuated replication, confirming the pathway's importance.

Conclusions:

• The Tpl2/AP-1 signaling pathway is a critical positive regulator of MHV-68 lytic replication.
• Tpl2 promotes viral replication through AP-1-dependent upregulation of key viral genes like RTA.
• Understanding this pathway offers insights into gammaherpesvirus pathogenesis and potential therapeutic targets.