Project Details
Abstract
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
External Project ID:NSC102-2628-B182-006-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/15 → 31/07/16 |
Keywords
- KSHV
- ORF50 protein
- MLN4924
- NEDD8
- protein stability
- ubiquitin
- Sp1
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