title: RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement.
abstract: The CC-chemokine RANTES (regulated on activation normal T-cell expressed and secreted; CCL5) transduces multiple intracellular signals. Like all chemokines, it stimulates G protein-coupled receptor (GPCR) activity through interaction with its cognate chemokine receptor(s), but in addition also activates a GPCR-independent signaling pathway. Here, we show that the latter pathway is mediated by an interaction between RANTES and glycosaminoglycan chains of CD44. We provide evidence that this association, at both low, physiologically relevant, and higher, probably supraphysiologic concentrations of RANTES, induces the formation of a signaling complex composed of CD44, src kinases, and adapter molecules. This triggers the activation of the p44/42 mitogen-activated protein kinase (MAPK) pathway. By specifically reducing CD44 expression using RNA interference we were able to demonstrate that the p44/p42 MAPK activation by RANTES requires a high level of CD44 expression. As well as potently inhibiting the entry of CCR5 using HIV-1 strains, RANTES can enhance HIV-1 infectivity under certain experimental conditions. This enhancement process depends in part on the activation of p44/p42 MAPK. Here we show that silencing of CD44 in HeLa-CD4 cells prevents the activation of p44/p42 MAPK and leads to a substantial reduction in HIV-1 infectivity enhancement by RANTES.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University Hospital, Zurich, Switzerland.
authors.forename: Branka
authors.initials: B
authors.lastname: Roscic-Mrkic
authors.forename: Marek
authors.initials: M
authors.lastname: Fischer
authors.forename: Christine
authors.initials: C
authors.lastname: Leemann
authors.forename: Amapola
authors.initials: A
authors.lastname: Manrique
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Gordon
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Amanda E I
authors.initials: AE
authors.lastname: Proudfoot
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
mesh_terms: D018946:Chemokine CCL5 / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D015497:HIV-1 / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011509:Proteoglycans / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053667:Syndecans; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018946:Chemokine CCL5; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D019707:Receptors, Chemokine; D053667:Syndecans; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases