The release of enveloped viruses is restricted by the innate immune defence component bone marrow stromal antigen 2 (BST2), which retains virions at the surface of infected cells. Viruses counteract the activity of BST2 by displacing it from the plasma membrane and, in some cases, promoting its lysosomal degradation. In HIV-1, the latter is achieved through the accessory protein Vpu, which recruits E3 ligase adaptors, such as β-TrCP1 and β-TrCP2, to BST2 for its polyubiquitylation and subsequent downregulation. The molecular details underlying ubiquitylation of BST2 are still unclear, and prompted Katy Janvier and colleagues (p. 1596), to screen for E3 ligases involved in this process. The authors find that depletion of the HECT E3 ligase NEDD4 and the membrane-associated RING-CH 8 (MARCH8) E3 ligase decreases BST2 ubiquitylation and impairs its sorting for degradation. However, NEDD4 and MARCH8 are not required for Vpu-dependent ubiquitylation and downregulation of BST2, but rather, Vpu controls the association of BST2 with β-TrCP to induce its downregulation. Taken together, these data suggest that Vpu-mediated downregulation of BST2 is achieved by bypassing the constitutive ubiquitylation and sorting machinery for BST2 and instead delivering it to β-TrCP for its cell surface downregulation and degradation, thereby providing an alternative route for the viral protein to counteract the host defence.