Abstract
The mouse cytomegalovirus M33 protein is highly homologous to mammalian G protein-coupled receptors (GPCRs) yet functions in an agonist-independent manner to activate a number of classical GPCR signal transduction pathways. M33 is functionally similar to the human cytomegalovirus-encoded US28 GPCR in its ability to induce inositol phosphate accumulation, activate NF-kappaB, and promote smooth muscle cell migration. This ability to promote cellular migration suggests a role for viral GPCRs like M33 in viral dissemination in vivo, and accordingly, M33 is required for efficient murine cytomegalovirus replication in the mouse. Although previous studies have identified several M33-induced signaling pathways, little is known regarding the membrane-proximal events involved in signaling and regulation of this receptor. In this study, we used recombinant retroviruses to express M33 in wild-type and Galpha(q/11)(-/-) mouse embryonic fibroblasts and show that M33 couples directly to the G(q/11) signaling pathway to induce high levels of total inositol phosphates in an agonist-independent manner. Our data also show that GRK2 is a potent regulator of M33-induced G(q/11) signaling through its ability to phosphorylate M33 and sequester Galpha(q/11) proteins. Taken together, the results from this study provide the first genetic evidence of a viral GPCR coupling to a specific G protein signaling pathway as well as identify the first viral GPCR to be regulated specifically by both the catalytic activity of the GRK2 kinase domain and the Galpha(q/11) binding activity of the GRK2 RH domain.
Highlights
To be expressed in the human genome [1]
This finding suggests that GRK2 can sequester GTP-bound G␣q/11 and inhibit G protein-coupled receptors (GPCRs) signaling independent of receptor phosphorylation [17, 18]
The M33 Amino Terminus and NRY Motif Are Required for Stimulation of Inositol Phosphate Accumulation—In this study we investigated the G protein coupling and G protein-coupled receptor kinase (GRK) regulation employed by the viral M33 GPCR during signal transduction
Summary
To be expressed in the human genome [1]. GPCRs are present in virtually all free-living organisms and have been found in numerous viruses including those in the herpesvirus family [2,3,4]. Our data suggest that M33 retains the characteristic agonist-independent signaling activity observed from other viral GPCRs such as US28, it is dually regulated by GRK2 similar to various host cell Gq/11-coupled receptors.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
