Abstract
The interferon-induced transmembrane protein BST-2/CD317 (tetherin) restricts the release of diverse enveloped viruses from infected cells. The HIV-1 accessory protein Vpu antagonizes this restriction by an unknown mechanism that likely involves the down-regulation of BST-2 from the cell surface. Here, we show that the optimal removal of BST-2 from the plasma membrane by Vpu requires the cellular protein β-TrCP, a substrate adaptor for a multi-subunit SCF E3 ubiquitin ligase complex and a known Vpu-interacting protein. β-TrCP is also required for the optimal enhancement of virion-release by Vpu. Mutations in the DSGxxS β-TrCP binding-motif of Vpu impair both the down-regulation of BST-2 and the enhancement of virion-release. Such mutations also confer dominant-negative activity, consistent with a model in which Vpu links BST-2 to β-TrCP. Optimal down-regulation of BST-2 from the cell surface by Vpu also requires the endocytic clathrin adaptor AP-2, although the rate of endocytosis is not increased; these data suggest that Vpu induces post-endocytic membrane trafficking events whose net effect is the removal of BST-2 from the cell surface. In addition to its marked effect on cell-surface levels, Vpu modestly decreases the total cellular levels of BST-2. The decreases in cell-surface and intracellular BST-2 are inhibited by bafilomycin A1, an inhibitor of endosomal acidification; these data suggest that Vpu induces late endosomal targeting and partial degradation of BST-2 in lysosomes. The Vpu-mediated decrease in surface expression is associated with reduced co-localization of BST-2 and the virion protein Gag along the plasma membrane. Together, the data support a model in which Vpu co-opts the β-TrCP/SCF E3 ubiquitin ligase complex to induce endosomal trafficking events that remove BST-2 from its site of action as a virion-tethering factor.
Highlights
HIV-1 encodes specific proteins dedicated to counteracting host cell ‘‘restriction factors’’ that inhibit viral replication [1]
The data suggest that Vpu recruits the cellular protein b-TrCP to modulate the trafficking of BST-2 within internal cellular membranes, removing BST-2 from its apparent site of action at the cell surface
Vpu-mediated down-regulation of BST-2 from the cell surface is partly dependent on the plasma membrane associated clathrin adaptor protein complex AP-2 and can be inhibited by disruption of the endo-lysosomal pH gradient. These data suggest that Vpu recruits b-TrCP to induce ubiquitinmediated endosomal trafficking events that reduce the levels of BST-2 on the plasma membrane, effectively removing BST-2 from its site of action as a virion-tethering factor
Summary
HIV-1 encodes specific proteins dedicated to counteracting host cell ‘‘restriction factors’’ that inhibit viral replication [1]. In the prototypic example of this relationship, the accessory protein Vif, found in almost all lentiviruses, targets cytidine deaminases in the APOBEC family for proteasomal degradation [2]; these cellular enzymes would otherwise damage nascent viral cDNAs to inhibit infectivity [3]. In the second example of this host-pathogen relationship, the accessory protein Vpu, found almost exclusively in HIV-1 and SIVcpz, counteracts the cellular transmembrane protein BST-2/CD317 (tetherin) [4,5]. BST-2 is an interferon-induced, cellsurface and lipid-raft associated protein that tethers nascent, fully formed HIV-1 virions to infected cells, preventing their release and subsequent spread [4,5,6,7,8]. How Vpu reduces the levels of BST-2 at the cell-surface is currently unknown
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