The Transmembrane Domain of BST-2 Determines Its Sensitivity to Down-Modulation by Human Immunodeficiency Virus Type 1 Vpu

Liang, Rong; Zhang, Jianyong; Lu, Jennifer; Pan, Qinghua; Lorgeoux, René-Pierre; Aloysius, Claudette; Guo, Fei; Liu, Shan-Lu; Wainberg, Mark A.; Liang, Chen

doi:10.1128/jvi.00620-09

Cited by 109 publications

(188 citation statements)

References 30 publications

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“…The cytoplasmic tail is involved in AP-2-dependent endocytosis of the molecule (28,43), while the transmembrane domain provides specificity for interaction with and downregulation by Vpu (11,12,23,24,30). Disulfide-linked dimerization of tetherin is required for restriction (28).…”

Section: Discussionmentioning

confidence: 99%

“…Vpu leads to surface downregulation and proteasomal degradation of CD4 in infected T cells and macrophages (23,34,40,41) and enhances viral particle release in restrictive cell types (16,38). Vpu overcomes tetherin-mediated restriction via an interaction facilitated through their respective transmembrane (TM) domains (12,13,24,30). The potential mechanisms accounting for tetherin surface downregulation by Vpu include proteasomal and lysosomal degradation together with sequestration of tetherin within the transGolgi network (TGN) (5).…”

mentioning

confidence: 99%

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The Tetherin/BST-2 Coiled-Coil Ectodomain Mediates Plasma Membrane Microdomain Localization and Restriction of Particle Release

Hammonds

Ding

Chu

et al. 2012

J Virol

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Tetherin/BST-2 forms a proteinaceous tether that restricts the release of a number of enveloped viruses following viral budding. Tetherin is an unusual membrane glycoprotein with two membrane anchors and an extended coiled-coil ectodomain. The ectodomain itself forms an imperfect coil that may undergo conformational shifts to accommodate membrane dynamics during the budding process. The coiled-coil ectodomain is required for restriction, but precisely how it contributes to the restriction of particle release remains under investigation. In this study, mutagenesis of the ectodomain was used to further define the role of the coiled-coil ectodomain in restriction. Scanning mutagenesis throughout much of the ectodomain failed to disrupt the ability of tetherin to restrict HIV particle release, indicating a high degree of plasticity. Targeted N-and C-terminal substitutions disrupting the coiled coil led to both a loss of restriction and an alteration of subcellular distribution. Two ectodomain mutants deficient in restriction were endocytosed inefficiently, and the levels of these mutants on the cell surface were significantly enhanced. An ectodomain mutant with four targeted serine substitutions (4S) failed to cluster in membrane microdomains, was deficient in restriction of particle release, and exhibited an increase in lateral mobility on the membrane. These results suggest that the tetherin ectodomain contributes to microdomain localization and to constrained lateral mobility. We propose that focal clustering of tetherin via ectodomain interactions plays a role in restriction of particle release.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Tetherin/BST-2 Coiled-Coil Ectodomain Mediates Plasma Membrane Microdomain Localization and Restriction of Particle Release

Hammonds

Ding

Chu

et al. 2012

J Virol

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“…39,40 Sequence variations in the TM domain of tetherin that affect sensitivity to Vpu have been identified. 41,42 Formation of Vpu/tetherin hetero-oligomers through direct interactions between their TM domains may therefore be essential for Vpu function, and these hetero-oligomers may be structurally related to Vpu homo-oligomers. A proposed therapeutic strategy is to use ''decoy'' peptides to sequester Vpu through formation of unproductive hetero-oligomers, allowing tetherin to inhibit viral release from infected cells even in the presence of Vpu.…”

Section: Introductionmentioning

confidence: 99%

Oligomerization state and supramolecular structure of the HIV‐1 Vpu protein transmembrane segment in phospholipid bilayers

et al. 2010

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HIV-1 Vpu is an 81-residue protein with a single N-terminal transmembrane (TM) helical segment that is involved in the release of new virions from host cell membranes. Vpu and its TM segment form ion channels in phospholipid bilayers, presumably by oligomerization of TM helices into a pore-like structure. We describe measurements that provide new constraints on the oligomerization state and supramolecular structure of residues 1-40 of Vpu (Vpu 1-40 ), including analytical ultracentrifugation measurements to investigate oligomerization in detergent micelles, photo-induced crosslinking experiments to investigate oligomerization in bilayers, and solid-state nuclear magnetic resonance measurements to obtain constraints on intermolecular contacts between and orientations of TM helices in bilayers. From these data, we develop molecular models for Vpu TM oligomers. The data indicate that a variety of oligomers coexist in phospholipid bilayers, so that a unique supramolecular structure can not be defined. Nonetheless, since oligomers of various sizes have similar intermolecular contacts and orientations, molecular models developed from our data are most likely representative of Vpu TM oligomers that exist in host cell membranes.

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“…After IFN-g treatment, a 3-fold increase in mRNA and greater than 2-fold increase in protein were observed. Induction of tetherin by IFNs in non-neuronal cells has been studied by many authors in different cell types and concluded to be cell type-dependant (Neil et al, 2007;Van Damme et al, 2008;Miyagi et al, 2009;Rong et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Interferon-Induced Tetherin Restricts Vesicular Stomatitis Virus Release in Neurons

Sarojini

Theofanis

Reiss

2011

DNA and Cell Biology

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Tetherin, a recently identified interferon (IFN)-inducible, type 2 transmembrane protein, has been shown to be a cellular antiviral restriction factor that retains newly formed virions in infected cells. Thus, tetherin plays an important role in the innate cell-autonomous immune response. The aim of this study was to examine the antiviral activities of tetherin in vesicular stomatitis virus infections of murine neuronal cells. Both IFN-b and IFN-g induce the expression of tetherin mRNA and protein. Tetherin knockdown experiments were carried out by transfection of tethrin shRNA into murine neuroblastoma cells using a vector containing the pCMV-driven tGFP gene. The efficiency of transfection was monitored through GFP expression by the transfected cells. Selected transfected cells were used for further mRNA and protein analysis, fluorescent immunocytolocalization, and viral infection to study the impact of tetherin knockdown. Our research indicates that tetherin is expressed on the outer face of the plasma membrane of murine neuroblastoma cells, its expression can be induced with both IFN-g and IFN-b, and tetherin restricts progeny virus release up to 100-fold in mammalian neurons, thus contributing to a potent antiviral state within the host cell.

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The Transmembrane Domain of BST-2 Determines Its Sensitivity to Down-Modulation by Human Immunodeficiency Virus Type 1 Vpu

Cited by 109 publications

References 30 publications

The Tetherin/BST-2 Coiled-Coil Ectodomain Mediates Plasma Membrane Microdomain Localization and Restriction of Particle Release

The Tetherin/BST-2 Coiled-Coil Ectodomain Mediates Plasma Membrane Microdomain Localization and Restriction of Particle Release

Oligomerization state and supramolecular structure of the HIV‐1 Vpu protein transmembrane segment in phospholipid bilayers

Interferon-Induced Tetherin Restricts Vesicular Stomatitis Virus Release in Neurons

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