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Functional Analysis of the Murine Cytomegalovirus G Protein-coupled Receptor M33

Sherrill, Joseph D.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225745444

Abstract Details

2008, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry, and Microbiology.
Several members of the herpesvirus family encode seven transmembrane-spanning proteins that share significant homology with the cellular G protein-coupled receptors (GPCRs). These viral GPCR homologs stimulate both G protein-dependent and G protein-independent signaling pathways reminiscent of cellular GPCRs. By mimicking host cell proteins and altering intricate signaling networks, viral GPCRs are often viewed as immune evasion genes, enhancing viral replication and persistence within the infected host. The studies described herein characterize the signaling activities and regulation of the viral GPCR homolog M33 encoded by the murine cytomegalovirus (MCMV). Cytomegaloviruses are species-specific opportunistic pathogens that cause disease within the immunocompromised host. MCMV has been used extensively as a model for studying human cytomegalovirus (HCMV) pathogenesis in vivo, with M33 playing an essential role in MCMV dissemination and replication within the host salivary gland. We have identified the first ten amino acids of M33 as critical for proper M33 post-translational modification, cell surface expression, as well as the activation of G protein signaling events. We show through mutational analysis that a conserved GPCR signaling motif of M33 is required for G protein signaling yet is not involved in other M33 signaling activities including phosphorylation of the mitogen-activated protein kinase p38 and activation of the transcription factor NF-κB, indicating M33 possesses G protein-independent signaling abilities. Additionally, we have identified a role of cellular GPCR regulatory proteins in attenuating M33 G protein signaling through a dual mechanism involving both receptor phosphorylation and sequestration of activated G proteins. Lastly, in order to understand M33 signaling and regulation in the context of MCMV infection we made various mutations of the M33 ORF within the MCMV genome and show that M33 and its ability to activate a Gq/11/PLC-β/PKC pathway appears to be required for efficient MCMV replication within the salivary gland. Further characterizations of these recombinant viruses will ultimately allow for the study of M33 function with regards to its contribution in MCMV pathogenesis in vivo. By understanding the G protein signaling pathways and regulatory events characteristic of viral GPCRs we may attain a greater appreciation of these processes as potential therapeutic targets for treating HCMV infection.
William Miller, PhD (Committee Chair)
Rhonda Cardin, PhD (Committee Member)
Gary Dean, PhD (Committee Member)
Rhett Kovall, PhD (Committee Member)
Alison Weiss, PhD (Committee Member)
145 p.
Biochemistry; Microbiology; Molecular Biology; Virology
G protein; GPCR; cytomegalovirus; MCMV; M33; CREB; protein kinase C

Recommended Citations

Citations

  • Sherrill, J. D. (2008). Functional Analysis of the Murine Cytomegalovirus G Protein-coupled Receptor M33 [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225745444

    APA Style (7th edition)

  • Sherrill, Joseph. Functional Analysis of the Murine Cytomegalovirus G Protein-coupled Receptor M33. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225745444.

    MLA Style (8th edition)

  • Sherrill, Joseph. "Functional Analysis of the Murine Cytomegalovirus G Protein-coupled Receptor M33." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225745444

    Chicago Manual of Style (17th edition)

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© 2008, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.