SIV Nef Proteins Recruit the AP-2 Complex to Antagonize Tetherin and Facilitate Virion Release

Zhang, Fengwen; Landford, Wilmina N.; Ng, Melinda; McNatt, Matthew W.; Bieniasz, Paul D.; Hatziioannou, Théodora

doi:10.1371/journal.ppat.1002039

Cited by 61 publications

(65 citation statements)

References 58 publications

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“…In contrast, SIV Nef and HIV-2 Env do not mediate tetherin degradation but rather lead to tetherin's intracellular sequestration following enhanced internalization from the surface. This is dependent on AP2 binding sites in both viral proteins (18,(36)(37)(38)49). For Nef (36) and also for Env, as shown here, this does not require the presence of the endocytic signal in tetherin itself.…”

Section: Discussionsupporting

confidence: 51%

“…Most SIVs that lack a vpu gene antagonize their species' tetherins with Nef (15,16). SIVmac Nef binds to the cytoplasmic tail of macaque tetherin and likely forms a ternary complex with clathrin adaptor protein complex 2 (AP2) (36,37) to stimulate tetherin endocytosis and intracellular sequestration. Nef's specificity for primate tetherins depends on a (G/D)DIWK motif that is absent from human tetherin.…”

Section: Resultsmentioning

confidence: 99%

“…However, a serine-threonine motif found only in L-tetherin has been highlighted as important (35). In contrast, other lentiviral tetherin antagonists do not mediate its degradation but rather promote its endocytosis from the PM for intracellular sequestration (15,18,(36)(37)(38).…”

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confidence: 99%

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Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

Weinelt

Neil

2014

J Virol

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The mammalian antiviral membrane protein tetherin (BST2/CD317) can be expressed as two isoforms derived from differential translational initiation. The shorter isoform of the human protein (S-tetherin) lacks the first 12 amino acids of the longer (Ltetherin) cytoplasmic tail, which includes a tyrosine motif that acts as both an endocytic recycling signal and a determinant of virus-induced NF-B activation. S-tetherin is also reported to be less sensitive to the prototypic viral antagonist human immunodeficiency virus type 1 (HIV-1) Vpu. Here we analyzed the relative sensitivities of L-and S-tetherins to primate lentiviral countermeasures. We show that the reduced sensitivity of S-tetherin to HIV-1 Vpu is a feature of all group M proteins, including those of transmitted founder viruses, primarily because it cannot be targeted for endosomal degradation owing to the truncation of its cytoplasmic tail. In contrast, both isoforms of the human and rhesus macaque tetherins display the same sensitivity to nondegradative lentiviral countermeasures of HIV-2 and SIVmac, respectively. Surprisingly, however, the Vpu proteins encoded by simian immunodeficiency viruses (SIVs) of African guenons, as well as that from recently isolated highly pathogenic HIV-1 group N, do not discriminate between tetherin isoforms. Together, these data suggest that the group M HIV-1 Vpu primarily adapted to target L-tetherin upon zoonotic transmission from chimpanzees, and further, we speculate that functions specifically associated with this isoform, such as proinflammatory signaling, play key roles in human tetherin's antiviral function in vivo. IMPORTANCEThe ability of HIV-1 and related viruses to counteract a host antiviral protein, tetherin, is strictly maintained. The adaptation of the HIV-1 Vpu protein to counteract human tetherin is thought to have been one of the key events in the establishment of the HIV/AIDS pandemic. Recent evidence shows that tetherin is expressed as two isoforms and that Vpu preferentially targets the longer form. Here we show that unlike other virus-encoded countermeasures, such as those from primate viruses related to HIV-1, the enhanced ability to counteract the long tetherin isoform is conserved among HIV-1 strains that make up the majority of the human pandemic. This correlates with the ability of Vpu to induce long tetherin degradation. We speculate that functions associated with the human version of this isoform, such as an inflammatory signaling capacity, selected for Vpu's enhanced targeting of long tetherin during its adaptation to humans.

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Section: Discussionsupporting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

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Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

Weinelt

Neil

2014

J Virol

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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%

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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“…SIV Nef counteracts the tetherin proteins of apes and Old World monkeys but not humans through the recognition of residues in the N-terminal cytoplasmic domain ((G/D 14 )DIWK 18 in rhesus macaque, sooty mangabey, and chimpanzee tetherin) that are missing in human tetherin (61,68). SIV cpz , SIV mac , and SIV agm Nef proteins down-modulate the tetherin proteins of their respective hosts from the cell surface by AP-2-dependent endocytosis (69). The nature of the molecular interactions between Nef and tetherin and the ultimate fate of tetherin in SIV-infected cells remain to be defined.…”

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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SIV Nef Proteins Recruit the AP-2 Complex to Antagonize Tetherin and Facilitate Virion Release

Cited by 61 publications

References 58 publications

Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

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

The Restriction Factors of Human Immunodeficiency Virus

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