Filamin A Protein Interacts with Human Immunodeficiency Virus Type 1 Gag Protein and Contributes to Productive Particle Assembly

• Published in: The Journal of biological chemistry 2011-08, Vol.286 (32), p.28498-28510
• Main Authors: Cooper, JoAnn, Liu, Ling, Woodruff, Elvin A., Taylor, Harry E., Goodwin, J. Shawn, D'Aquila, Richard T., Spearman, Paul, Hildreth, James E.K., Dong, Xinhong
• Format: Article
• Language: English
• Subjects: Actin; Clathrin - genetics; Clathrin - metabolism; Contractile Proteins - genetics; Contractile Proteins - metabolism; Cytoskeleton; Endocytosis - genetics; Filamin A; Filamins; gag Gene Products, Human Immunodeficiency Virus; Gene Library; HeLa Cells; HIV; HIV Infections - genetics; HIV Infections - mortality; HIV Infections - transmission; HIV-1 - pathogenicity; HIV-1 - physiology; Humans; Microbiology; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Plasma Membrane; Protein Transport - genetics; Saccharomyces cerevisiae; Trafficking; Two-Hybrid System Techniques; Virus Assembly - drug effects; Virus Assembly - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.239053

HIV-1 Gag precursor directs virus particle assembly and release. In a search for Gag-interacting proteins that are involved in late stages of the HIV-1 replication cycle, we performed yeast two-hybrid screening against a human cDNA library and identified the non-muscle actin filament cross-linking protein filamin A as a novel Gag binding partner. The 280-kDa filamin A regulates cortical actin network dynamics and participates in the anchoring of membrane proteins to the actin cytoskeleton. Recent studies have shown that filamin A facilitates HIV-1 cell-to-cell transmission by binding to HIV receptors and coreceptors and regulating their clustering on the target cell surface. Here we report a novel role for filamin A in HIV-1 Gag intracellular trafficking. We demonstrate that filamin A interacts with the capsid domain of HIV-1 Gag and that this interaction is involved in particle release in a productive manner. Disruption of this interaction eliminated Gag localization at the plasma membrane and induced Gag accumulation within internal compartments. Moreover, blocking clathrin-dependent endocytic pathways did not relieve the restriction to particle release induced by filamin A depletion. These results suggest that filamin A is involved in the distinct step of the Gag trafficking pathway. The discovery of the Gag-filamin A interaction may provide a new therapeutic target for the treatment of HIV infection.