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Journal of Virology, October 2006, p. 9697-9709, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00746-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Lytic Switch Protein Stimulates DNA Binding of RBP-Jk/CSL To Activate the Notch Pathway

Kyla Driscoll Carroll,1 Wei Bu,1 Diana Palmeri,1 Sophia Spadavecchia,1 Stephen J. Lynch,1,{dagger} Salvatore A. E. Marras,2 Sanjay Tyagi,2 and David M. Lukac1*

Department of Microbiology and Molecular Genetics, Graduate School of Biomedical Sciences,1 Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey2

Received 12 April 2006/ Accepted 18 July 2006

Kaposi's sarcoma-associated herpesvirus (KSHV) lytic switch protein, Rta, is a ligand-independent inducer of the Notch signal transduction pathway, and KSHV cannot reactivate from latency in cells null for the Notch target protein RBP-Jk. Here we show that Rta promotes DNA binding of RBP-Jk, a mechanism that is fundamentally different from that established for the RBP-Jk-activating proteins, Notch intracellular domain (NICD) and Epstein-Barr virus EBNA2. Although constitutively active RBP-Jk and NICD do not transactivate KSHV promoters independently, cotransfection of an Rta mutant lacking its transactivation domain robustly restores transcriptional activation. Cooperation requires intact DNA binding sites for Rta and RBP-Jk and trimeric complex formation between the three molecules in vitro. In infected cells, RBP-Jk is virtually undetectable on a series of viral and cellular promoters during KSHV latency but is significantly enriched following Rta expression during viral reactivation. Accordingly, Rta, but not EBNA2 and NICD, reactivates the complete viral lytic cycle.

* Corresponding author. Mailing address: P.O. Box 1709, ICPH E350C, Newark, NJ 07101. Phone: (973) 972-4483, ext. 20907. Fax: (973) 972-8981. E-mail: Lukacdm{at}umdnj.edu.

{dagger} Present address: Department of Molecular Neurobiology, New York University Medical Center, New York, NY.

Journal of Virology, October 2006, p. 9697-9709, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00746-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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