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Journal of Virology, July 2009, p. 6727-6738, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00351-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus RTA Promotes Degradation of the Hey1 Repressor Protein through the Ubiquitin Proteasome Pathway{triangledown}

Faye Gould,1,2 Sally M. Harrison,1,2 Eric W. Hewitt,1,2 and Adrian Whitehouse1,2*

Institute of Molecular and Cellular Biology, Faculty of Biological Sciences,1 Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom2

Received 17 February 2009/ Accepted 2 April 2009

The Kaposi's sarcoma-associated herpesvirus (KSHV) replication and transcription activator (RTA) protein regulates the latent-lytic switch by transactivating a variety of KSHV lytic and cellular promoters. RTA is a novel E3 ubiquitin ligase that targets a number of transcriptional repressor proteins for degradation by the ubiquitin proteasome pathway. Herein, we show that RTA interacts with the cellular transcriptional repressor protein Hey1. We demonstrate that Hey1 is a target for RTA-mediated ubiquitination and is subsequently degraded by the proteasome. Moreover, a Cys-plus-His-rich region within RTA is important for RTA-mediated degradation of Hey1. We confirm that Hey1 represses the RTA promoter and, furthermore, show that Hey1 binds to the RTA promoter. An interaction was observed between Hey1 and the corepressor mSin3A, and this interaction was abolished in the presence of RTA. Additionally, mSin3A associated with the RTA promoter in nonreactivated, but not reactivated, BCBL1 cells. Small interfering RNA knockdown of Hey1 in HEK 293T cells latently infected with the recombinant virus rKSHV.219 led to increased levels of RTA expression upon reactivation but was insufficient to induce complete lytic reactivation. These results suggest that other additional transcriptional repressors are also important in maintenance of KSHV latency. Taken together, our results suggest that Hey1 has a contributory role in the maintenance of KSHV latency and that disruption of the Hey1 repressosome by RTA-targeted degradation may be one step in the mechanism to regulate lytic reactivation.

* Corresponding author. Mailing address: Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom. Phone: 44 113 3437096. Fax: 44 113 3435638. E-mail: a.whitehouse{at}leeds.ac.uk

{triangledown} Published ahead of print on 15 April 2009.

Journal of Virology, July 2009, p. 6727-6738, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00351-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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