The cytosolic N-terminus of CD317/tetherin is a membrane microdomain exclusion motif

Billcliff, Peter G.; Gorleku, Oforiwa A; Chamberlain, Luke H.; Banting, George

doi:10.1242/bio.20135793

Cited by 13 publications

(18 citation statements)

References 56 publications

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“…Crosslinking of BST-2 by virion tethering or antibody binding can trigger activation of the NF-jB pathway as well as overexpression of BST-2 [23,24,34], presumably due to the resultant clustering of BST-2 in the lipid raft microdomains. Alternatively, it has been suggested these lipid raft microdomains themselves may act as signaling platforms, and the role of BST-2 in maintaining and organizing these rafts may therefore be indirectly responsible for signaling activity [20].…”

Section: Discussionmentioning

confidence: 99%

“…This apparent discrepancy raised the possibility that the observed effects of BST-2 were occurring via different pathways. Indeed, multiple functions have been ascribed to BST-2, including interaction with the cytoskeleton and organization of membrane microdomains [3,[19][20][21] as well as viral sensing and intracellular signaling [22][23][24][25]. Our investigation into how BST-2 may have inhibited influenza virus reverse genetics led us to the demonstration that BST-2 is capable of down-regulating transient protein expression and identification of a potential novel BST-2 antiviral mechanism.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An unconventional BST-2 function: Down-regulation of transient protein expression

Narkpuk

Wanitchang

Kramyu

et al. 2014

Biochemical and Biophysical Research Communications

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An unconventional BST-2 function: Down-regulation of transient protein expression

Narkpuk

Wanitchang

Kramyu

et al. 2014

Biochemical and Biophysical Research Communications

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“…Bsr GI digestion of pcDNA-Clover removed the initial stop codon of the fluorochrome coding sequence, thereby enabling the correct expression of the Clover-BST-2 fused protein. Since the membrane localization signal of BST-2 is determined by both the anchor signal located in the transmembrane domain and the GPI-anchor, addressing of the BST-2 fusion protein is not disrupted in those conditions [26,28]. …”

Section: Methodsmentioning

confidence: 99%

“…Viral particles are then susceptible to internalization into endosomal compartments and undergo subsequent degradation [17,18,23,24,25]. Structurally BST-2 is a type II integral membrane protein, with the N-terminus inside the cell cytoplasm, a single membrane spanning domain, and a C-terminus modified by the addition of an unusual GPI (glycosylphosphatidylinositol) anchor [26,27,28,29,30]. …”

Section: Introductionmentioning

confidence: 99%

Single Amino Acid Substitution N659D in HIV-2 Envelope Glycoprotein (Env) Impairs Viral Release and Hampers BST-2 Antagonism

Dufrasne

Lombard

Goubau

et al. 2016

Viruses

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BST-2 or tetherin is a host cell restriction factor that prevents the budding of enveloped viruses at the cell surface, thus impairing the viral spread. Several countermeasures to evade this antiviral factor have been positively selected in retroviruses: the human immunodeficiency virus type 2 (HIV-2) relies on the envelope glycoprotein (Env) to overcome BST-2 restriction. The Env gp36 ectodomain seems involved in this anti-tetherin activity, however residues and regions interacting with BST-2 are not clearly defined. Among 32 HIV-2 ROD Env mutants tested, we demonstrated that the asparagine residue at position 659 located in the gp36 ectodomain is mandatory to exert the anti-tetherin function. Viral release assays in cell lines expressing BST-2 showed a loss of viral release ability for the HIV-2 N659D mutant virus compared to the HIV-2 wild type virus. In bst-2 inactivated H9 cells, those differences were lost. Subtilisin treatment of infected cells demonstrated that the N659D mutant was more tethered at the cell surface. Förster resonance energy transfer (FRET) experiments confirmed a direct molecular link between Env and BST-2 and highlighted an inability of the mutant to bind BST-2. We also tested a virus presenting a truncation of 109 amino acids at the C-terminal part of Env, a cytoplasmic tail partial deletion that is spontaneously selected in vitro. Interestingly, viral release assays and FRET experiments indicated that a full Env cytoplasmic tail was essential in BST-2 antagonism. In HIV-2 infected cells, an efficient Env-mediated antagonism of BST-2 is operated through an intermolecular link involving the asparagine 659 residue as well as the C-terminal part of the cytoplasmic tail.

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“…Recent studies have also suggested that the linkage of tetherin with the cortical actin network plays a role in the organization of lipid rafts (22,23). However, the mechanism of how the cortical actin network is involved in tetherin location and tetherin antiviral activity remains to be determined.…”

mentioning

confidence: 99%

Filamin A Is Involved in HIV-1 Vpu-mediated Evasion of Host Restriction by Modulating Tetherin Expression

Dotson

Woodruff

Villalta

et al. 2016

Journal of Biological Chemistry

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Tetherin, also known as bone marrow stromal antigen 2 (BST-2), inhibits the release of a wide range of enveloped viruses, including human immunodeficiency virus, type 1 (HIV-1) by directly tethering nascent virions to the surface of infected cells. The HIV-1 accessary protein Vpu counteracts tetherin restriction via sequestration, down-regulation, and/or displacement mechanisms to remove tetherin from sites of virus budding. However, the exact mechanism of Vpu-mediated antagonism of tetherin restriction remains to be fully understood. Here we report a novel role for the actin cross-linking regulator filamin A (FLNa) in Vpu anti-tetherin activities. We demonstrate that FLNa associates with tetherin and that FLNa modulates tetherin turnover. FLNa deficiency was found to enhance cell surface and steady-state levels of tetherin expression. In contrast, we observed that overexpression of FLNa reduced tetherin expression levels both on the plasma membrane and in intracellular compartments. Although FLNb shows high amino acid sequence similarity with FLNa, we reveal that only FLNa, but not FLNb, plays an essential role in tetherin turnover. We further showed that FLNa deficiency inhibited Vpu-mediated enhancement of virus release through interfering with the activity of Vpu to down-regulate cellular tetherin. Taken together, our studies suggest that Vpu hijacks the FLNa function in the modulation of tetherin to neutralize the antiviral factor tetherin. These findings may provide novel strategies for the treatment of HIV-1 infection.

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The cytosolic N-terminus of CD317/tetherin is a membrane microdomain exclusion motif

Cited by 13 publications

References 56 publications

An unconventional BST-2 function: Down-regulation of transient protein expression

An unconventional BST-2 function: Down-regulation of transient protein expression

Single Amino Acid Substitution N659D in HIV-2 Envelope Glycoprotein (Env) Impairs Viral Release and Hampers BST-2 Antagonism

Filamin A Is Involved in HIV-1 Vpu-mediated Evasion of Host Restriction by Modulating Tetherin Expression

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