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Endocytic activity of HIV-1 Vpu: Phosphoserine-dependent interactions with clathrin adaptors.

Authors
  • Stoneham, Charlotte A1, 2
  • Singh, Rajendra1, 2
  • Jia, Xiaofei3
  • Xiong, Yong3
  • Guatelli, John1, 2
  • 1 Department of Medicine, University of California at San Diego, La Jolla, California.
  • 2 VA San Diego Healthcare System, San Diego, California.
  • 3 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut.
Type
Published Article
Journal
Traffic
Publisher
Wiley (Blackwell Publishing)
Publication Date
Aug 01, 2017
Volume
18
Issue
8
Pages
545–561
Identifiers
DOI: 10.1111/tra.12495
PMID: 28504462
Source
Medline
Keywords
License
Unknown

Abstract

HIV-1 Vpu modulates cellular transmembrane proteins to optimize viral replication and provide immune-evasion, triggering ubiquitin-mediated degradation of some targets but also modulating endosomal trafficking to deplete them from the plasma membrane. Interactions between Vpu and the heterotetrameric clathrin adaptor protein (AP) complexes AP-1 and AP-2 have been described, yet the molecular basis and functional roles of such interactions are incompletely defined. To investigate the trafficking signals encoded by Vpu, we fused the cytoplasmic domain (CD) of Vpu to the extracellular and transmembrane domains of the CD8 α-chain. CD8-VpuCD was rapidly endocytosed in a clathrin- and AP-2-dependent manner. Multiple determinants within the Vpu CD contributed to endocytic activity, including phosphoserines of the β-TrCP binding site and a leucine-based ExxxLV motif. Using recombinant proteins, we confirmed ExxxLV-dependent binding of the Vpu CD to the α/σ2 subunit hemicomplex of AP-2 and showed that this is enhanced by serine-phosphorylation. Remarkably, the Vpu CD also bound directly to the medium (μ) subunits of AP-2 and AP-1; this interaction was dependent on serine-phosphorylation of Vpu and on basic residues in the μ subunits. We propose that the flexibility with which Vpu binds AP complexes broadens the range of cellular targets that it can misdirect to the virus' advantage.

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