Vpu antagonizes BST-2-mediated restriction of HIV-1 release via β-TrCP and endo-lysosomal trafficking

Richard S. Mitchell, Chris Katsura, Mark A. Skasko, Katie Fitzpatrick, David Lau, Autumn Schulze, Edward B. Stephens, Florence Margottin-Goguet, Richard Benarous, John C. Guatelli

Research output: Contribution to journalArticle

234 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1000450
JournalPLoS Pathogens
Volume5
Issue number5
DOIs
StatePublished - May 1 2009
Externally publishedYes

Fingerprint

HIV-1
Virion
SKP Cullin F-Box Protein Ligases
Ubiquitin-Protein Ligases
Down-Regulation
Proteins
Vesicular Transport Adaptor Proteins
Cell Membrane
gag Gene Products
Mutation
Endocytosis
Lysosomes
Interferons
Viruses
Membranes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Mitchell, R. S., Katsura, C., Skasko, M. A., Fitzpatrick, K., Lau, D., Schulze, A., ... Guatelli, J. C. (2009). Vpu antagonizes BST-2-mediated restriction of HIV-1 release via β-TrCP and endo-lysosomal trafficking. PLoS Pathogens, 5(5), [e1000450]. https://doi.org/10.1371/journal.ppat.1000450

Vpu antagonizes BST-2-mediated restriction of HIV-1 release via β-TrCP and endo-lysosomal trafficking. / Mitchell, Richard S.; Katsura, Chris; Skasko, Mark A.; Fitzpatrick, Katie; Lau, David; Schulze, Autumn; Stephens, Edward B.; Margottin-Goguet, Florence; Benarous, Richard; Guatelli, John C.

In: PLoS Pathogens, Vol. 5, No. 5, e1000450, 01.05.2009.

Research output: Contribution to journalArticle

Mitchell, RS, Katsura, C, Skasko, MA, Fitzpatrick, K, Lau, D, Schulze, A, Stephens, EB, Margottin-Goguet, F, Benarous, R & Guatelli, JC 2009, 'Vpu antagonizes BST-2-mediated restriction of HIV-1 release via β-TrCP and endo-lysosomal trafficking', PLoS Pathogens, vol. 5, no. 5, e1000450. https://doi.org/10.1371/journal.ppat.1000450
Mitchell, Richard S. ; Katsura, Chris ; Skasko, Mark A. ; Fitzpatrick, Katie ; Lau, David ; Schulze, Autumn ; Stephens, Edward B. ; Margottin-Goguet, Florence ; Benarous, Richard ; Guatelli, John C. / Vpu antagonizes BST-2-mediated restriction of HIV-1 release via β-TrCP and endo-lysosomal trafficking. In: PLoS Pathogens. 2009 ; Vol. 5, No. 5.
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AU - Lau, David

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