title: Filamin-A regulates actin-dependent clustering of HIV receptors.
abstract: Human immunodeficiency virus (HIV)-1 infection requires envelope (Env) glycoprotein gp120-induced clustering of CD4 and coreceptors (CCR5 or CXCR4) on the cell surface; this enables Env gp41 activation and formation of a complex that mediates fusion between Env-containing and target-cell membranes. Kinetic studies show that viral receptors are actively transported to the Env-receptor interface in a process that depends on plasma membrane composition and the actin cytoskeleton. The mechanisms by which HIV-1 induces F-actin rearrangement in the target cell remain largely unknown. Here, we show that CD4 and the coreceptors interact with the actin-binding protein filamin-A, whose binding to HIV-1 receptors regulates their clustering on the cell surface. We found that gp120 binding to cell receptors induces transient cofilin-phosphorylation inactivation through a RhoA-ROCK-dependent mechanism. Blockade of filamin-A interaction with CD4 and/or coreceptors inhibits gp120-induced RhoA activation and cofilin inactivation. Our results thus identify filamin-A as an adaptor protein that links HIV-1 receptors to the actin cytoskeleton remodelling machinery, which may facilitate virus infection.
authors.affiliation: Department of Immunology and Oncology Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Jiménez-Baranda
authors.forename: Concepción
authors.initials: C
authors.lastname: Gómez-Moutón
authors.forename: Ana
authors.initials: A
authors.lastname: Rojas
authors.forename: Lorena
authors.initials: L
authors.lastname: Martínez-Prats
authors.forename: Emilia
authors.initials: E
authors.lastname: Mira
authors.forename: Rosa
authors.initials: R
authors.lastname: Ana Lacalle
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.forename: Antonella
authors.initials: A
authors.lastname: Viola
authors.forename: Rafael
authors.initials: R
authors.lastname: Delgado
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-A
authors.forename: Santos
authors.initials: S
authors.lastname: Mañes
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000502:physiology*; D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D003285:Contractile Proteins / Q000502:physiology*; D064448:Filamins; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008840:Microfilament Proteins / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D015704:CD4 Antigens; D003285:Contractile Proteins; D064448:Filamins; D015699:HIV Envelope Protein gp120; D008840:Microfilament Proteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D020742:rhoA GTP-Binding Protein