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Journal of Virology, May 2009, p. 4423-4434, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02274-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Interaction of the Gammaherpesvirus 68 orf73 Protein with Cellular BET Proteins Affects the Activation of Cell Cycle Promoters{triangledown}

Matthias Ottinger,1,2,§* Daniel Pliquet,1,§ Thomas Christalla,1 Ronald Frank,3 James P. Stewart,4 and Thomas F. Schulz1*

Institut für Virologie, Medizinische Hochschule Hannover, Hannover, Germany,1 Department of Pathology, Harvard Medical School, Boston, Massachusetts,2 Helmholz Zentrum für Infektionsforschung, Abteilung Chemische Biologie, Braunschweig, Germany,3 School of Infection and Host Defence, The University of Liverpool, Liverpool, United Kingdom4

Received 29 October 2008/ Accepted 16 February 2009

Infection of mice with murine gammaherpesvirus 68 (MHV-68) provides a valuable animal model for gamma-2 herpesvirus (rhadinovirus) infection and pathogenesis. The MHV-68 orf73 protein has been shown to be required for the establishment of viral latency in vivo. This study describes a novel transcriptional activation function of the MHV-68 orf73 protein and identifies the cellular bromodomain containing BET proteins Brd2/RING3, Brd3/ORFX, and BRD4 as interaction partners for the MHV-68 orf73 protein. BET protein members are known to interact with acetylated histones, and Brd2 and Brd4 have been implicated in fundamental cellular processes, including cell cycle regulation and transcriptional regulation. Using MHV-68 orf73 peptide array assays, we identified Brd2 and Brd4 interaction sites in the orf73 protein. Mutation of one binding site led to a loss of the interaction with Brd2/4 but not the retinoblastoma protein Rb, to impaired chromatin association, and to a decreased ability to activate the BET-responsive cyclin D1, D2, and E promoters. The results therefore pinpoint the binding site for Brd2/4 in a rhadinoviral orf73 protein and suggest that the recruitment of a member of the BET protein family allows the MHV-68 orf73 protein to activate the promoters of G1/S cyclins. These findings point to parallels between the transcriptional activator functions of rhadinoviral orf73 proteins and papillomavirus E2 proteins.

* Corresponding author. Mailing address for Thomas F. Schulz: Institut für Virologie, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany. Phone: 49-511-532-6736. Fax: 49-511-532-8736. E-mail: schulz.thomas{at}mh-hannover.de. Mailing address for Matthias Ottinger: Department of Pathology, Harvard Medial School, 77 Ave. Louis Pasteur, NRB 952, Boston, MA 02115. Phone: (617) 432-0743. Fax: (617) 432-2218. E-mail: Matthias_Ottinger{at}hms.harvard.edu

{triangledown} Published ahead of print on 25 February 2009.

§ These authors contributed equally.

Journal of Virology, May 2009, p. 4423-4434, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02274-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • You, J., Li, Q., Wu, C., Kim, J., Ottinger, M., Howley, P. M. (2009). Regulation of Aurora B Expression by the Bromodomain Protein Brd4. Mol. Cell. Biol. 29: 5094-5103 [Abstract] [Full Text]  


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