Figure 5

Unified model of Vpu-mediated cell-surface Tetherin downregulation. Tetherin traffics along the anterograde trafficking pathway and reaches the plasma membrane. The protein is endocytosed in clathrin-coated pits, transported to the TGN and most probably recycles back to the cell surface. Upon expression of Vpu, Tetherin is forming complexes with the viral protein, thus trapping the restriction factor in the TGN, away from sites of viral assembly at the plasma membrane where Tetherin is cross-linking progeny virions. Vpu could intercept endocytosed Tetherin as well as Tetherin arriving from the ER although this remains to be determined. Subsequently, Vpu could induce Tetherin ubiquitination through recruitment of β-TrCP-2, leading to a stronger retention in the TGN. Sequestered ubiquitinated Tetherin conjugates could ultimately be targeted for proteosomal and/or lysosomal degradation. As such, Vpu-mediated Tetherin degradation may represent a complementary mechanism that Vpu could exploit to reach optimal Tetherin antagonism, perhaps, in specific cellular environments.