title: Herpes simplex virus enhances chemokine function through modulation of receptor trafficking and oligomerization.
abstract: Glycoprotein G (gG) from herpes simplex virus 1 and 2 (HSV-1 and HSV-2, important human neurotropic pathogens) is the first viral chemokine-binding protein found to potentiate chemokine function. Here we show that gG attaches to cell surface glycosaminoglycans and induces lipid raft clustering, increasing the incorporation of CXCR4 receptors into these microdomains. gG induces conformational rearrangements in CXCR4 homodimers and changes their intracellular partners, leading to sustained, functional chemokine/receptor complexes at the surface. This results in increased chemotaxis dependent on the cholesterol content of the plasma membrane and receptor association to Src-kinases and phosphatidylinositol-3-kinase signalling pathways, but independent of clathrin-mediated endocytosis. Furthermore, using electron microscopy, we show that such enhanced functionality is associated with the accumulation of low-order CXCR4 nanoclusters. Our results provide insights into basic mechanisms of chemokine receptor function and into a viral strategy of immune modulation.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: Nadia
authors.initials: N
authors.lastname: Martinez-Martin
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Viejo-Borbolla
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Martín
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Blanco
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
authors.affiliation: Institute for Research in Biomedicine, Bellinzona 6500, Switzerland.
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.affiliation: 1] Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain [2] Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcamí
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D016000:Cluster Analysis; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism; D004705:Endocytosis; D005679:G(M3) Ganglioside / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D018258:Herpesvirus 2, Human / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D010316:Particle Size; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018925:Chemokines; D002966:Clathrin; D005679:G(M3) Ganglioside; D006023:Glycoproteins; D006025:Glycosaminoglycans; D019718:Receptors, CXCR4; D010768:Phosphoserine