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Characterization of E3 ligases involved in lysosomal sorting of the HIV-1 restriction factor BST2.

Authors
  • Roy, Nicolas1, 2, 3
  • Pacini, Grégory1, 2, 3
  • Berlioz-Torrent, Clarisse1, 2, 3
  • Janvier, Katy4, 2, 3
  • 1 Inserm, U1016, Institut Cochin, Paris, France. , (France)
  • 2 CNRS, UMR8104, Paris, France. , (France)
  • 3 Université Paris Descartes, Sorbonne Paris Cité, Paris, France. , (France)
  • 4 Inserm, U1016, Institut Cochin, Paris, France [email protected] , (France)
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
May 01, 2017
Volume
130
Issue
9
Pages
1596–1611
Identifiers
DOI: 10.1242/jcs.195412
PMID: 28320822
Source
Medline
Keywords
License
Unknown

Abstract

The cellular protein BST2 (also known as 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 polyubiquitylation of BST2, a post-translation modification required for Vpu-induced BST2 downregulation, through recruitment of the E3 ligase complex SCF adaptors β-TrCP1 and β-TrCP2 (two isoforms encoded by BTRC and FBXW11, respectively). Herein, we further investigate the role of the ubiquitylation machinery in the lysosomal sorting of BST2. Using a small siRNA screen, we highlighted two additional regulators of BST2 constitutive ubiquitylation and sorting to the lysosomes: the E3 ubiquitin ligases NEDD4 and MARCH8. Interestingly, Vpu does not hijack the cellular machinery that is constitutively involved in BST2 ubiquitylation to sort BST2 for degradation in the lysosomes but instead promotes the recognition of BST2 by β-TrCP proteins. Altogether, our results provide further understanding of the mechanisms underlying BST2 turnover in cells.

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