HIV-1 Vpu Protein Antagonizes Innate Restriction Factor BST-2 via Lipid-embedded Helix-Helix Interactions

Skasko, Mark; Wang, Yan; Tian, Ye; Tokarev, Andrey; Munguia, Jason; Ruiz, Autumn; Stephens, Edward B.; Opella, Stanley J.; Guatelli, John

doi:10.1074/jbc.m111.296772

Cited by 101 publications

(151 citation statements)

References 32 publications

(63 reference statements)

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“…It is separated into a *9 aa N-terminal ectodomain, a single TMD and a cytosolic domain containing two (or more) a-helices (aa 33-49 and 57-70) . Peptides corresponding to the first *30 aa recapitulate channel activity in vitro, and both the TMD and the cytosolic domain interact with CD4 and tetherin, independent of channel activity (Bolduan et al, 2011;Kuhl et al, 2011;Skasko et al, 2012). NMR structures for both the cytosolic domain (PDB ID: 1VPU, 2K7Y) and TMD (PDB ID: 2JPX, 2GOF, 2GOH, 1PJE) are available, which have been assembled into computational models of the full-length protein ; a more recent version of this model is shown in Fig.…”

Section: Hiv-1 Vpumentioning

confidence: 99%

Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

119

146

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The channel-forming activity of a family of small, hydrophobic integral membrane proteins termed 'viroporins' is essential to the life cycles of an increasingly diverse range of RNA and DNA viruses, generating significant interest in targeting these proteins for antiviral development. Viroporins vary greatly in terms of their atomic structure and can perform multiple functions during the virus life cycle, including those distinct from their role as oligomeric membrane channels. Recent progress has seen an explosion in both the identification and understanding of many such proteins encoded by highly significant pathogens, yet the prototypic M2 proton channel of influenza A virus remains the only example of a viroporin with provenance as an antiviral drug target. This review attempts to summarize our current understanding of the channel-forming functions for key members of this growing family, including recent progress in structural studies and drug discovery research, as well as novel insights into the life cycles of many viruses revealed by a requirement for viroporin activity. Ultimately, given the successes of drugs targeting ion channels in other areas of medicine, unlocking the therapeutic potential of viroporins represents a valuable goal for many of the most significant viral challenges to human and animal health.

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Section: Hiv-1 Vpumentioning

confidence: 99%

Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

119

146

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“…NMR structural data and computational modeling have provided a high-resolution picture of the transmembrane interface between Vpu and tetherin that represents a promising target for drug design (70,71). Pharmaceutical disruption of this interface would, in principle, render HIV-1 susceptible to restriction by tetherin, significantly attenuating viral replication in vivo.…”

Section: Restriction By Particle Tethering: Bst-2/tetherin Integral Mmentioning

confidence: 99%

The Restriction Factors of Human Immunodeficiency Virus

Harris

Hultquist

Evans

2012

Journal of Biological Chemistry

244

255

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Cellular proteins called "restriction factors" can serve as powerful blockades to HIV replication, but the virus possesses elaborate strategies to circumvent these barriers. First, we discuss general hallmarks of a restriction factor. Second, we review how the viral Vif protein protects the viral genome from lethal levels of cDNA deamination by promoting APOBEC3 protein degradation; how the viral Vpu, Env, and Nef proteins facilitate internalization and degradation of the virus-tethering protein BST-2/tetherin; and how the viral Vpx protein prevents the premature termination of reverse transcription by degrading the dNTPase SAMHD1. These HIV restriction and counter-restriction mechanisms suggest strategies for new therapeutic interventions. Restriction Factor HallmarksRestriction factors have at least four defining characteristics (see Fig. 1A). First and foremost, a restriction factor must directly and dominantly cause a significant decrease in HIV infectivity. This is often determined by cotransfecting cell lines such as HEK293 and HeLa with a molecular clone of the virus, with or without a plasmid expressing the restriction factor, and measuring the amount and infectivity of virus recovered in the cell culture medium after 1-2 days of incubation. Such assays are ideally done over a range of restriction factor expression, with the highest levels often imposing log-scale drops in viral infectivity (see Fig. 1B). This "single-cycle" assay for viral replication is useful for testing the impact of viral mutations and/or restriction factor variations.Second, if a restriction factor is a true threat to viral replication, then the predecessors of HIV invariably evolved an equally potent counter-restriction mechanism that still exists in the present day virus. For instance, titrating a counter-restriction factor into the aforementioned single-cycle infectivity experiment can result in a full recovery of viral infectivity despite the presence of an active restriction factor (Fig. 1B). Viruses lacking these various countermeasures are able to replicate in some, but not all, cell types depending on the expression level of the relevant restriction factor. Cell lines that support replication are termed "permissive," and those that do not are termed "nonpermissive." This life/death dichotomy has been elegantly exploited to identify several restriction factors and their corresponding viral antagonists.Third, because the interactions between restriction and counter-restriction factors occur through direct protein-protein interactions, the restriction factor often shows signatures of rapid evolution. In general, mutations are maintained in a population only if they confer a selective advantage. If a host species experiences iterative rounds of pathogenic pressure, altered variants of host restriction factors that are no longer susceptible to the pathogen's counteraction mechanism are selected. Over evolutionary time, this results in an overabundance of amino acid substitution mutations in these genes relative to non-amino acid...

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“…Vpu-mutants W76G, S52N,S56N ϩ W76G, and the transmembrane domain mutant A10F,A14F,A18F (which does not bind BST2) permitted co-patching of Env and BST2 to levels near that of ⌬Vpu (p values of 0.0810, 0.2486, and 0.7940, respectively, by unpaired t test), indicating that these mutants are impaired in their ability to displace BST2 from sites of viral assembly. For Vpu-A10F,A14F,A18F, this impairment presumably relates to its inability to bind BST2 (6).…”

Section: Mutation Of Vpu Trp-76 To Glycine Specifically Impairsmentioning

confidence: 99%

“…BST2 entraps lipid enveloped virions as they bud from the plasma membrane, preventing their release. Vpu, a single-pass type I transmembrane protein (3), binds directly to BST2, a single-pass type II transmembrane protein with a glycosylphosphatidylinositol anchor (4), via an anti-parallel interaction between the proteins' transmembrane domains (5)(6)(7)(8)(9). This interaction enables Vpu to decrease the concentration of BST2 on the plasma membrane and induce the degradation of BST2 by an endolysosomal mechanism (7, 8, 10 -13).…”

mentioning

confidence: 99%

Membrane Anchoring by a C-terminal Tryptophan Enables HIV-1 Vpu to Displace Bone Marrow Stromal Antigen 2 (BST2) from Sites of Viral Assembly

Lewinski

Jafari²,

Zhang

et al. 2015

Journal of Biological Chemistry

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Background: HIV-1 Vpu displaces bone marrow stromal antigen 2 (BST2) from sites of viral assembly. Results: A tryptophan residue near the C terminus of Vpu is required for this activity and interacts with the lipid bilayer. Conclusion: Interaction of the C terminus of Vpu with the lipid bilayer helps HIV-1 escape restriction by BST2. Significance: The topology of the cytoplasmic domain of Vpu with respect to the lipid bilayer is a key aspect of BST2 antagonism.

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HIV-1 Vpu Protein Antagonizes Innate Restriction Factor BST-2 via Lipid-embedded Helix-Helix Interactions

Cited by 101 publications

References 32 publications

Viroporins: structure, function and potential as antiviral targets

Viroporins: structure, function and potential as antiviral targets

The Restriction Factors of Human Immunodeficiency Virus

Membrane Anchoring by a C-terminal Tryptophan Enables HIV-1 Vpu to Displace Bone Marrow Stromal Antigen 2 (BST2) from Sites of Viral Assembly

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