The cellular protein BST2/ Tetherin acts as a major intrinsic antiviral protein that prevents the release of enveloped viruses by trapping nascent viral particles at the surface of infected cells. Viruses have evolved specific strategies to displace BST2 from viral budding sites in order to promote virus egress. In HIV-1, the accessory protein Vpu counters BST2 antiviral activity and promotes sorting of BST2 for lysosomal degradation. Vpu increases poly-ubiquitination of BST2 through recruitment of the E3 ligase complex SCF adaptor β-TrCP, a post translation modification required for Vpu-induced BST2 down-regulation. Herein, we further investigated the role of the ubiquitination machinery in the lysosomal sorting of BST2. Using a small siRNA screen we highlighted two additional regulators of BST2 constitutive ubiquitination and sorting to the lysosomes: the E3 ubiquitin ligases NEDD4 and MARCH8. Interestingly, Vpu does not hijack the cellular machinery constitutively involved in BST2 ubiquitination to sort BST2 for degradation in the lysosomes, but instead promotes the recognition of BST2 by β-TrCP. Altogether, our results provide further understanding of the mechanisms underlying BST2 turnover in cells.
- Received July 22, 2016.
- Accepted February 17, 2017.
- © 2017. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.