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Journal of Virology, February 2008, p. 1884-1898, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02550-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Functional Analysis of the Murine Cytomegalovirus Chemokine Receptor Homologue M33: Ablation of Constitutive Signaling Is Associated with an Attenuated Phenotype In Vivo{triangledown}

Ruth Case,1 Emma Sharp,1 Tau Benned-Jensen,2 Mette M. Rosenkilde,2 Nicholas Davis-Poynter,1,3* and Helen E. Farrell1,3

Animal Health Trust, Lanwades Park, Kentford, Suffolk, United Kingdom,1 Laboratory for Molecular Pharmacology, Institute of Neuroscience and Pharmacology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark,2 Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital and Clinical Medical Virology Centre, University of Queensland, Herston, Queensland, Australia3

Received 20 November 2006/ Accepted 20 November 2007

The murine cytomegalovirus (MCMV) M33 gene is conserved among all betaherpesviruses and encodes a homologue of seven-transmembrane receptors (7TMR) with the capacity for constitutive signaling. Previous studies have demonstrated that M33 is important for MCMV dissemination to or replication within the salivary glands. In this study, we probed N- and C-terminal regions of M33 as well as known 7TMR signature motifs in transmembrane (TM) II and TM III to determine the impact on cell surface expression, constitutive signaling, and in vivo phenotype. The region between amino acids R340 and A353 of the C terminus was found to be important for CREB- and NFAT-mediated signaling, although not essential for phosphatidylinositol turnover. Tagging or truncation of the N terminus of M33 resulted in loss of cell surface expression. Within TM II, an F79D mutation abolished constitutive signaling, demonstrating a role, as in other cellular and viral 7TMR, of TM II in receptor activation. In TM III, the arginine (but not the asparagine) residue of the NRY motif (the counterpart of the common DRY motif in cellular 7TMR) was found to be essential for constitutive signaling. Selected mutations incorporated into recombinant MCMV showed that disruption of constitutive signaling for a viral 7TMR homologue resulted in a reduced capacity to disseminate to or replicate in the salivary glands. In addition, HCMV UL33 was found to partially compensate for the lack of M33 in vivo, suggesting conserved biological roles of the UL33 gene family.

* Corresponding author. Mailing address: Clinical Medical Virology Centre, University of Queensland, Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital, Herston 4029, Queensland, Australia. Phone: 671 36368138. Fax: 617 36361401. E-mail: n.davispoynter{at}uq.edu.au

{triangledown} Published ahead of print on 5 December 2007.

Journal of Virology, February 2008, p. 1884-1898, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02550-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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