Regulation of the Expression and Function of Kaposi's Sarcoma-Associated Herpesvirus ORF50 Protein

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

Project Details


Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that is associated with at least three human malignancies: Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Like all herpesviruses, KSHV manifests two distinct phases of its life cycle, latency and the lytic cycle. The switch between latency and the lytic cycle is important not only for viral propagation but also for viral pathogenesis. The KSHV ORF50 protein, a multifunctional transcription activator, is the key controller for viral reactivation from latency. Thus far, the regulatory mechanisms underlying the transcriptional and post-translational controls of the ORF50 protein are still not fully understood. Our current investigation finds that treatment of latently KSHV-infected cells with MLN4924, an inhibitor of NEDD8-activating enzyme, activates the transcription of ORF50 gene and its downstream lytic events. Additionally, our study reveals that multiple regulatory motifs within ORF50 protein are responsible for controlling the protein abundance. The control of the ORF50 protein abundance is mediated through the proteasome degradation pathway. The importance of each regulatory motif in controlling the ORF50 protein level remains to be characterized. Besides being a transcriptional activator, our new findings show that ORF50 protein can act as a transcriptional repressor on specific cellular and viral gene promoters that contains Sp1-binding sites. The role of Sp1 protein in the ORF50-mediated transcriptional repression needs to be addressed. Here, we propose three aims in this project. These aims extend our previous findings and include: a) determining the regulatory mechanism of KSHV reactivation induced by MLN4924, b) studying the regulatory mechanism of ORF50 protein stability, and c) determining the regulatory mechanism of the ORF50-mediated transcriptional repression. Because of the importance of ORF50 protein in the latent-lytic switch, elucidating the regulation of its gene activation, protein stability, and its repressive function will provide further insights into the viral development and pathogenesis.

Project IDs

Project ID:PC10401-0207
External Project ID:NSC102-2628-B182-006-MY3
Effective start/end date01/08/1531/07/16


  • KSHV
  • ORF50 protein
  • MLN4924
  • NEDD8
  • protein stability
  • ubiquitin
  • Sp1


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