Abstract
The Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma, body cavity-based lymphoma, and Castleman disease. vIRF-3 is a KSHV latent gene that is critical for proliferation of KSHV-positive lymphoid cells. Furthermore, vIRF-3 contributes to KSHV-associated pathogenesis by stimulating c-Myc transcription activity. Here we show that vIRF-3 can associate with Skp2, a key component of the SCF(skp2) ubiquitin ligase complex. Skp2 is a transcriptional co-factor for c-Myc that was shown to regulate the stability of c-Myc protein as well as c-Myc-dependent transcription. In this study, we show that vIRF-3 binds to the F-box of Skp2 and recruits it to c-Myc-regulated promoters to activate c-Myc-dependent transcription. Additionally, cells overexpressing vIRF-3 exhibit higher levels of c-Myc ubiquitylation, suggesting that ubiquitylation is necessary for c-Myc-mediated transcription. Moreover, vIRF-3 can stabilize the c-Myc protein by increasing its half-life. Collectively, these results indicate that vIRF-3 can effectively manipulate c-Myc stability and function and thus contribute to c-Myc-induced KSHV-associated lymphomagenesis.
Highlights
The Kaposi sarcoma-associated herpesvirus (KSHV)-encoded vIRF-3 is a multifunctional protein expressed in latently infected primary effusion lymphoma
We show that the KSHV latent oncoprotein, vIRF-3, can stabilize c-Myc protein and that vIRF3-mediated recruitment of c-Myc and its co-factor, Skp2, to c-Myc-regulated promoters can efficiently enhance c-Myc-dependent transcription
We found that the vIRF-3-expressing stable line, BJAB/ vIRF-3, shows reproducibly higher expression of endogenous c-Myc protein when compared with the control BJAB/vector line (Fig. 1A)
Summary
The KSHV-encoded vIRF-3 is a multifunctional protein expressed in latently infected primary effusion lymphoma. Results: vIRF-3 associates with Skp ubiquitin ligase and stimulates the ubiquitylation and transcription activity of c-Myc. Conclusion: vIRF-3 activates the c-Myc-regulated pathway that may lead to oncogenic transformation. The Skp ubiquitin ligase is required for induction of c-Myc-responsive genes, suggesting that ubiquitylation promotes c-Myc turnover and stimulates its transcription activity (16 –19). We show that the KSHV latent oncoprotein, vIRF-3, can stabilize c-Myc protein and that vIRF3-mediated recruitment of c-Myc and its co-factor, Skp, to c-Myc-regulated promoters can efficiently enhance c-Myc-dependent transcription. VIRF-3 Regulates c-Myc Function and Stability ing that ubiquitylation is necessary for c-Myc-mediated transcription These results further demonstrate the importance of vIRF-3 in the activation of the c-Myc-regulated pathway that may lead to uncontrolled proliferation and oncogenic transformation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
