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Journal of Virology, February 2002, p. 1328-1338, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1328-1338.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Rat Cytomegalovirus R33-Encoded G Protein-Coupled Receptor Signals in a Constitutive Fashion

Yvonne K. Gruijthuijsen,1 Paola Casarosa,2 Suzanne J. F. Kaptein,1 Jos L. V. Broers,3 Rob Leurs,2 Cathrien A. Bruggeman,1 Martine J. Smit,2 and Cornelis Vink1*

Department of Medical Microbiology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6202 AZ Maastricht,1 Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Free University, 1081 HV Amsterdam,2 Department of Molecular Cell Biology, University of Maastricht, 6200 MD Maastricht, The Netherlands3

Received 27 August 2001/ Accepted 15 October 2001

The rat cytomegalovirus (RCMV) R33 gene is conserved among all betaherpesviruses and encodes a protein (pR33) that shows sequence similarity with chemokine-binding G protein-coupled receptors (GPCRs). Previously, the physiological significance of the R33 gene was demonstrated by the finding that an RCMV strain with R33 deleted is severely attenuated in vivo and is unable to either enter or replicate in the salivary glands of infected rats. Here, we report that RCMV pR33 is expressed as a functional GPCR that signals in an agonist-independent manner in both COS-7 and Rat2 cells. Transient expression of pR33 in COS-7 cells results in constitutive activation of phospholipase C (PLC) due to coupling to G proteins of the Gq class. Interestingly, PLC activation is partially inhibited by cotransfection with G{alpha}-transducin subunits, which indicates the involvement of Gß{gamma} as well as G{alpha} subunits in pR33-mediated signaling. Surprisingly, PLC activation is also partially inhibited by addition of pertussis toxin (PTX), suggesting that pR33 activates not only Gq but also Gi/0 proteins. The constitutive activation of Gi/0 proteins by pR33 is further demonstrated by the PTX-sensitive decrease of CRE-mediated transcription and the PTX-sensitive increase of both NF-{kappa}B- and SRE-mediated transcription. In contrast to its homolog of human herpesvirus 6B (pU12), pR33 does not bind RANTES.

* Corresponding author. Mailing address: Department of Medical Microbiology, University of Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31 43 3876669. Fax: 31 43 3876643. E-mail: kvi{at}lmib.azm.nl.

Journal of Virology, February 2002, p. 1328-1338, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1328-1338.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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