Abstract
In the field of herpesvirus research, the exact molecular mechanism by which such viruses reactivate from latency remains elusive. Kaposi's sarcoma-associated herpesvirus (KSHV) primarily exists in a latent state, while only 1–3% of cells support lytic infection at any specific time. KSHV reactivation from latency is an exceedingly intricate process mediated by the integration of viral and cellular factors. Previously, our lab has described early growth response-1 (Egr-1) as an essential component for the KSHV reactivation process via its ability to mediate transcription of KSHV ORF50, the gene encoding for replication and transcription activator (RTA), a viral component known to control the switch from latent to lytic infection. In here, electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) experiments revealed that Egr-1 binds KSHV ORF50 promoter (ORF50P) in at least two different GC-rich binding domains. Expression profiles of cellular egr-1 and KSHV-encoded ORF50 follow a similar pattern during de novo KSHV infection. Over-expressing Egr-1, a signaling component downstream of Raf>MEK>ERK1/2, in KSHV-infected cells activates KSHV lytic replication. Through performing more physiologically relevant experiments, we analyzed the effect of a dietary supplement containing resveratrol on KSHV-infected cells. Our results, for the first time, demonstrate resveratrol to act in lowering ERK1/2 activity and expression of Egr-1 in KSHV-infected cells, resulting in the suppression of virus reactivation from latency. Taken together, these findings will undoubtedly contribute to future studies on not only combating KSHV related disease conditions, but also on other herpesviruses-induced pathogenesis.
Highlights
Significant strides have been made since the discovery of Kaposi’s sarcoma-associated herpesvirus (KSHV) by Chang et al [1] nearly 20 years ago that have helped to increase our understanding of this infectious agent
Band shifts were not observed when ORF50 promoter (ORF50P) probes were incubated with in vitro transcribed and translated (IVT)-synthesized KSHV glycoprotein L
We did not observe any such differences in the binding affinity of early growth response-1 (Egr-1) to ORF50P3 and ORF50P8 by electrophoretic mobility shift assays (EMSA) using IVT Egr-1 (Fig. 1B, C)
Summary
Significant strides have been made since the discovery of Kaposi’s sarcoma-associated herpesvirus (KSHV) by Chang et al [1] nearly 20 years ago that have helped to increase our understanding of this infectious agent. KSHV is a c2-herpesvirus that has been directly linked to the development of Kaposi’s sarcoma (KS), primary effusion (PEL), and multicentric Castleman disease (MCD). This virus is closely related to Epstein-Barr virus (EBV), murine gammaherpesvirus-68, and herpesvirus saimiri [2]. As KSHV displays several characteristics shared among other herpesviruses, its ability to switch between latent and lytic stages of infection is of particular concern. Regulation of the switch between the two stages of infection is mediated by viral and cellular factors. The KSHV protein, replication and transcription activator (RTA), is known to be a crucial viral component controlling the transition from latency to a lytic infection [5]. Cellular early growth response-1 (Egr-1) protein was shown to be an important factor involved in KSHV reactivation through its ability to mediate transcription of KSHV ORF50, the gene encoding RTA [6]
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