title: Filamin A Is Involved in HIV-1 Vpu-mediated Evasion of Host Restriction by Modulating Tetherin Expression.
abstract: Tetherin, also known as bone marrow stromal antigen 2 (BST-2), inhibits the release of a wide range of enveloped viruses, including human immunodeficiency virus, type 1 (HIV-1) by directly tethering nascent virions to the surface of infected cells. The HIV-1 accessary protein Vpu counteracts tetherin restriction via sequestration, down-regulation, and/or displacement mechanisms to remove tetherin from sites of virus budding. However, the exact mechanism of Vpu-mediated antagonism of tetherin restriction remains to be fully understood. Here we report a novel role for the actin cross-linking regulator filamin A (FLNa) in Vpu anti-tetherin activities. We demonstrate that FLNa associates with tetherin and that FLNa modulates tetherin turnover. FLNa deficiency was found to enhance cell surface and steady-state levels of tetherin expression. In contrast, we observed that overexpression of FLNa reduced tetherin expression levels both on the plasma membrane and in intracellular compartments. Although FLNb shows high amino acid sequence similarity with FLNa, we reveal that only FLNa, but not FLNb, plays an essential role in tetherin turnover. We further showed that FLNa deficiency inhibited Vpu-mediated enhancement of virus release through interfering with the activity of Vpu to down-regulate cellular tetherin. Taken together, our studies suggest that Vpu hijacks the FLNa function in the modulation of tetherin to neutralize the antiviral factor tetherin. These findings may provide novel strategies for the treatment of HIV-1 infection.
authors.affiliation: From the Department of Microbiology and Immunology and Center for AIDS Health Disparities Research, School of Medicine, Meharry Medical College, Nashville, Tennessee 37208.
authors.forename: Dominique
authors.initials: D
authors.lastname: Dotson
authors.affiliation: From the Department of Microbiology and Immunology and Center for AIDS Health Disparities Research, School of Medicine, Meharry Medical College, Nashville, Tennessee 37208.
authors.forename: Elvin A
authors.initials: EA
authors.lastname: Woodruff
authors.affiliation: From the Department of Microbiology and Immunology and Center for AIDS Health Disparities Research, School of Medicine, Meharry Medical College, Nashville, Tennessee 37208.
authors.forename: Fernando
authors.initials: F
authors.lastname: Villalta
authors.affiliation: From the Department of Microbiology and Immunology and Center for AIDS Health Disparities Research, School of Medicine, Meharry Medical College, Nashville, Tennessee 37208 xdong@mmc.edu.
authors.forename: Xinhong
authors.initials: X
authors.lastname: Dong
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D064448:Filamins / Q000235:genetics / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*; D057074:Virus Release / Q000502:physiology*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D064448:Filamins; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
keywords: HIV-1 Vpu; endocytosis; filamin; lipid raft; protein turnover; tetherin; trafficking