Filamin-A regulates actin-dependent clustering of HIV receptors.
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.
Jiménez-Baranda
Sonia
S
Department of Immunology and Oncology Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain.
Gómez-Moutón
Concepción
C
Rojas
Ana
A
Martínez-Prats
Lorena
L
Mira
Emilia
E
Ana Lacalle
Rosa
R
Valencia
Alfonso
A
Dimitrov
Dimiter S
DS
Viola
Antonella
A
Delgado
Rafael
R
Martínez-A
Carlos
C
Mañes
Santos
S
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
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