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.
Highlights
IFN-inducible bone marrow stromal antigen 2 (BST-2, known as tetherin, CD317, and HM1.24) inhibits human immunodeficiency virus type 1 (HIV-1)2 release and spreads by trapping newly formed virions on the surface of infected cells [1, 2]
Expression of filamin A (FLNa)-specific siRNA in HeLa cells, either siRNAFLNa-1 or siRNAFLNa-2, efficiently decreased total cellular levels of endogenous FLNa by more than 80% compared with expression of control siRNA (Fig. 1E). siRNA-mediated knockdown of FLNa enhanced the levels of cellular tetherin (Fig. 1E) and surface tetherin (Fig. 1F)
We demonstrate that the actin-binding protein FLNa plays an important role in modulating tetherin expression at a posttranslational level
Summary
IFN-inducible bone marrow stromal antigen 2 (BST-2, known as tetherin, CD317, and HM1.24) inhibits human immunodeficiency virus type 1 (HIV-1)2 release and spreads by trapping newly formed virions on the surface of infected cells [1, 2]. The transient expression of FLNa in M2 cells reduced total cellular tetherin expression (Fig. 1D) and decreased the level of cell surface tetherin (data not shown). HeLa cells were transfected with FLNa-GFP expression plasmids, followed by immunofluorescence confocal microscopy.
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