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      Differential Ligand Binding to a Human Cytomegalovirus Chemokine Receptor Determines Cell Type–Specific Motility

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          Abstract

          While most chemokine receptors fail to cross the chemokine class boundary with respect to the ligands that they bind, the human cytomegalovirus (HCMV)-encoded chemokine receptor US28 binds multiple CC-chemokines and the CX 3C-chemokine Fractalkine. US28 binding to CC-chemokines is both necessary and sufficient to induce vascular smooth muscle cell (SMC) migration in response to HCMV infection. However, the function of Fractalkine binding to US28 is unknown. In this report, we demonstrate that Fractalkine binding to US28 not only induces migration of macrophages but also acts to inhibit RANTES-mediated SMC migration. Similarly, RANTES inhibits Fractalkine-mediated US28 migration in macrophages. While US28 binding of both RANTES and Fractalkine activate FAK and ERK-1/2, RANTES signals through Gα12 and Fractalkine through Gαq. These findings represent the first example of differential chemotactic signaling via a multiple chemokine family binding receptor that results in migration of two different cell types. Additionally, the demonstration that US28-mediated chemotaxis is both ligand-specific and cell type–specific has important implications in the role of US28 in HCMV pathogenesis.

          Author Summary

          Chemokines are small cytokines that are critical for recruiting and activating the cells of the immune system during viral infections. A number of viruses, including the large herpes virus human cytomegalovirus (HCMV), encode mechanisms to impede the effects of chemokines or have gained the ability to use these molecules to their own advantage. HCMV encodes multiple chemokine receptors including US28, which binds two different classes of chemokines namely the CC and CX 3C families. In this report, we demonstrate that US28 binding to a CC chemokine elicits different responses compared to when binding to Fractalkine, the only CX 3C chemokine. RANTES (CC chemokine) binding to US28 mediates smooth muscle cell migration, but Fractalkine blocks this process in a dose-dependent manner. However, Fractalkine binding to US28 can specifically mediate the migration of macrophages, another important cell type during viral pathogenesis. We explored the intracellular signaling pathways responsible for each migration event and determined that they differ in the G-proteins that are coupled to US28 following addition of ligand and that this occurs in a cell type–specific manner. These results provide a new mechanism for HCMV acceleration of vascular disease via the specific migration of macrophages and provide the first example of cell type–specific migration via multiple chemokines binding to a single receptor.

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          Most cited references31

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          Atherosclerosis. the road ahead.

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            Differential regulation of cell motility and invasion by FAK

            Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK−/− fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK−/− cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK−/− v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK–Src-p130Cas–Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways.
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              Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis.

              The hallmark of early atherosclerosis is the accumulation of lipid-laden macrophages in the subendothelial space. Circulating monocytes are the precursors of these "foam cells," and recent evidence suggests that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Fractalkine (FK) is a structurally unusual chemokine that can act either as a soluble chemotactic factor or as a transmembrane-anchored adhesion receptor for circulating leukocytes. A polymorphism in the FK receptor, CX(3)CR1, has been linked to a decrease in the incidence of coronary artery disease. To determine whether FK is critically involved in atherogenesis, we deleted the gene for CX(3)CR1 and crossed these mice into the apoE(-/-) background. Here we report that FK is robustly expressed in lesional smooth muscle cells, but not macrophages, in apoE(-/-) mice on a high-fat diet. CX(3)CR1(-/-) mice have a significant reduction in macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation. Taken together, these data provide strong evidence that FK plays a key role in atherogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                February 2009
                February 2009
                20 February 2009
                : 5
                : 2
                : e1000304
                Affiliations
                [1 ]Department of Molecular Microbiology and Immunology and The Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon, United States of America
                [2 ]Department of Immunology, The Scripps Research Institute, La Jolla, California, United States of America
                [3 ]Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry, Amsterdam, The Netherlands
                Harvard Medical School, United States of America
                Author notes

                Conceived and designed the experiments: JEV KF JAN DNS. Performed the experiments: JEV RMM JDP VD. Analyzed the data: JEV VD. Contributed reagents/materials/analysis tools: PPS JDP LH VD KF MS DDS. Wrote the paper: JEV JAN DNS.

                Article
                08-PLPA-RA-1194R2
                10.1371/journal.ppat.1000304
                2637432
                19229316
                57f74a19-9b34-413d-9c1a-c5ab142015ae
                Vomaske et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 6 October 2008
                : 20 January 2009
                Page count
                Pages: 12
                Categories
                Research Article
                Biochemistry/Cell Signaling and Trafficking Structures
                Cardiovascular Disorders/Cardiac Surgery and Transplantations
                Cell Biology/Cell Signaling
                Cell Biology/Cytoskeleton
                Virology/Virulence Factors and Mechanisms

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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