The replication and transcription activator of murine gammaherpesvirus 68 cooperatively enhances cytokine-activated, STAT3-mediated gene expression [Signal Transduction]

Gammaherpesviruses (γΗVs) have a dynamic strategy for life-time persistence, involving productive infection, latency, and intermittent reactivation. In latency reservoirs, such as B lymphocytes, γΗV exists as a viral episome and expresses few viral genes. Although the ability of γHV to reactivate from latency and re-enter the lytic phase is challenging to investigate and control, it is known that the γΗV replication and transcription activator, RTA, can promote lytic reactivation. In this study, we provide first evidence that RTA of murine γΗV 68 (MHV68) selectively binds and enhances the activity of tyrosine-phosphorylated host STAT3. STAT3 is a transcription factor classically activated by specific tyrosine 705-phosphorylation (pTyr705-STAT3) in response to cytokine stimulation. pTyr705-STAT3 forms a dimer that avidly binds a consensus target site in the promoters of regulated genes, and our results indicate that RTA cooperatively enhances the ability of pTyr705-STAT3 to induce expression of a STAT3 responsive reporter gene. As indicated by co-immunoprecipitation, in latently infected B cells that are stimulated to reactivate MHV68, RTA bound specifically to endogenous pTyr705-STAT3. An in vitro binding assay confirmed that RTA selectively recognizes pTyr705-STAT3 and indicated that the C-terminal transactivation domain of RTA was required for enhancing STAT3-directed gene expression. The cooperation of these transcription factors may influence both viral and host genes. During MHV68 de novo infection, pTyr705-STAT3 promoted the temporal expression of ORF59, a viral replication protein. Our results demonstrate that MHV68 RTA specifically recognizes and recruits activated pTyr705-STAT3 STAT3 during the lytic phase of infection.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2uNtZPL
via IFTTT