title: Membrane Anchoring by a C-terminal Tryptophan Enables HIV-1 Vpu to Displace Bone Marrow Stromal Antigen 2 (BST2) from Sites of Viral Assembly.
abstract: The restriction factor BST2 (tetherin) prevents the release of enveloped viruses from the host cell and is counteracted by HIV-1 Vpu. Vpu and BST2 interact directly via their transmembrane domains. This interaction enables Vpu to induce the surface down-regulation and the degradation of BST2, but neither of these activities fully accounts for the ability of Vpu to enhance virion release. During a study of naturally occurring Vpu proteins, we found that a tryptophan residue near the Vpu C terminus is particularly important for enhancing virion release. Vpu proteins with a W76G polymorphism degraded and down-regulated BST2 from the cell surface, yet they inefficiently stimulated virion release. Here we explore the mechanism of this anomaly. We find that Trp-76 is critical for the ability of Vpu to displace BST2 from sites of viral assembly in the plane of the plasma membrane. This effect does not appear to involve a general reorganization of the membrane microdomains associated with virion assembly, but rather is a specific effect of Vpu on BST2. Using NMR spectroscopy, we find that the cytoplasmic domain of Vpu and Trp-76 specifically interact with lipids. Moreover, paramagnetic relaxation enhancement studies show that Trp-76 inserts into the lipid. These data are consistent with a model whereby Trp-76 anchors the C terminus of the cytoplasmic tail of Vpu to the plasma membrane, enabling the movement of Vpu-bound BST2 away from viral assembly sites.
authors.affiliation: From the Departments of Medicine and the Veterans Affairs San Diego Healthcare System, San Diego, California 92161.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Lewinski
authors.affiliation: From the Departments of Medicine and.
authors.forename: Moein
authors.initials: M
authors.lastname: Jafari
authors.affiliation: Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0679 and.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0679 and sopella@ucsd.edu.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Opella
authors.affiliation: From the Departments of Medicine and the Veterans Affairs San Diego Healthcare System, San Diego, California 92161 jguatelli@ucsd.edu.
authors.forename: John
authors.initials: J
authors.lastname: Guatelli
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011110:Polymorphism, Genetic; D059748:Proteolysis; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*; D019065:Virus Assembly / Q000502:physiology*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
keywords: Cell Biology; Cell Surface Protein; Human Immunodeficiency Virus (HIV); Innate Immunity; Membrane Trafficking; Nuclear Magnetic Resonance (NMR); Retrovirus; Tryptophan