Reciprocal Regulation of Mdm2 and Orf50 in the Latent-To-Lytic Switch of Kaposi$S Sarcoma-Associated Herpesvirus

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details


Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gamma herpesvirus, which is closely associated with at least three human malignancies: Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Similar to all herpesviruses, KSHV manifests two distinct phases of its life cycle: latency and lytic cycle. The switch of KSHV from latency to lytic cycle is triggered by the expression of virally encoded ORF50 protein, which is a multifunctional replication and transcription activator. Therefore, to successfully sustain KSHV latency in infected cells, the virus must require hijacking of specific cellular pathways in order to repress ORF50 expression and maintain viral episome in the host cell. Despite extensive studies, there are many important questions that still remain unanswered in the control of the latent-to-lytic switch of KSHV, including how the ORF50 expression is restrained during the latent phase of infection and how the viral latency is disrupted by ORF50. In our preliminary results, we have shown that MDM2 oncoprotein interacts with ORF50 and promotes the protein degradation of ORF50. Inversely, ectopic ORF50 overexpression is also able to down-regulate MDM2 expression levels in KSHV-infected cells. The reciprocal regulation of MDM2 and ORF50 during the latent-to-lytic switch needs to be further investigated. In addition to the reciprocal repression between MDM2 and ORF50, we have also found that latency-associated nuclear antigen (LANA), the key regulator of KSHV latency, is linked to increased expression of MDM2 and YY1 in infected cells. As noted, YY1 behaves as a transcriptional repressor of KSHV orf50 gene. These findings strongly suggest that LANA may utilize at least two regulatory pathways, either through transcriptional silencing (YY1) or through protein degradation (MDM2), to repress the ORF50 expression. To test our hypothesis, we propose three specific aims in the research project. These specific aims include: 1) studying the role of MDM2 in the control of ORF50 protein stability, 2) investigating how ORF50 oppositely regulates MDM2 expression during KSHV lytic cycle, and 3) determining the actions of viral latent proteins on the expression of MDM2 and YY1. Understanding the regulatory network between viral and cellular factors in controlling the latent-to-lytic switch of KSHV is important not only for providing further insights into viral-host interaction, but also for offering opportunities for the development of new therapeutic strategies for the treatment of KSHV-associated diseases.

Project IDs

Project ID:PC10507-0239
External Project ID:MOST105-2320-B182-013
Effective start/end date01/08/1631/07/17


  • KSHV
  • ORF50
  • MDM2
  • protein stability
  • YY1
  • LANA


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