Serine-Threonine Ubiquitination Mediates Downregulation of BST-2/Tetherin and Relief of Restricted Virion Release by HIV-1 Vpu

Tokarev, Andrey; Munguia, Jason

doi:10.1128/jvi.01795-10

Cited by 112 publications

(137 citation statements)

References 46 publications

(64 reference statements)

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“…2E). In general, our results corroborate those reported in several recent manuscripts (27,32,35), which have each found that the two cytosolic lysines have no phenotype with respect to viral egress or surface down-regulation by Vpu. However, as described above, disagreement remains regarding the contribution that these lysines make toward Vpu-dependent ubiquitination.…”

Section: Vpu-dependent Bst-2 Ubiquitinationsupporting

confidence: 82%

“…These results suggest that either the Ser/Thr residues are not targeted by Vpu (regardless of the presence of Lys-18 and Lys-21) or that they are targeted by Vpu, but in their absence, Vpu-dependent ubiquitination/degradation of BST-2 can still take place, presumably by targeting other available residues. Tokarev et al (35) undertook an extensive mutational analysis of the BST-2 cytoplasmic domain and found that those mutants that included substitutions for the Ser/Thr residues were the most debilitated with respect to Vpu surface downregulation and tethering activity. Although this would appear to contradict our findings, they also showed data that the STS mutant was specifically ubiquitinated and degraded in the presence of Vpu, in agreement with our findings.…”

Section: Discussionmentioning

confidence: 99%

“…However, unlike WT BST-2, which they observed to be degraded by Vpu, the BST-2(K18R,K21R) protein remained stable in the presence of Vpu, leading them to conclude that Vpu particle release and BST-2 degradation functions are separable (34). Most recently, Tokarev et al (35) have provided the clearest demonstration that BST-2 is ubiquitinated in the presence of Vpu. However, even after making substitutions for all of BST-2 cytoplasmically exposed lysine, cysteine, serine, and threonine residues, BST-2 was still ubiquitinated and down-regulated by Vpu, albeit to a lesser degree than WT BST-2.…”

mentioning

confidence: 99%

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Ubiquitination of BST-2 Protein by HIV-1 Vpu Protein Does Not Require Lysine, Serine, or Threonine Residues within the BST-2 Cytoplasmic Domain

Gustin

Douglas

Bai

et al. 2012

Journal of Biological Chemistry

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Section: Vpu-dependent Bst-2 Ubiquitinationsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ubiquitination of BST-2 Protein by HIV-1 Vpu Protein Does Not Require Lysine, Serine, or Threonine Residues within the BST-2 Cytoplasmic Domain

Gustin

Douglas

Bai

et al. 2012

Journal of Biological Chemistry

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“…Tetherin antagonism by Vpu also depends in part on the recruitment of βTrCP-2, an adaptor protein for an E3 ubiquitin ligase involved in targeting tetherin for degradation (24,25,30,31). Hence, substitutions in a conserved DSGxxS motif in the cytoplasmic tail of Vpu (S52,56N) that prevent the recruitment of βTrCP-2 partially impair tetherin antagonism by preventing its degradation, but not its endosomal sequestration (25,(30)(31)(32)(33). These substitutions are also known to abrogate CD4 down-regulation, but do not affect Vpu-mediated down-modulation of NTB-A (23).…”

Section: Deletion Of Vpu Increases the Susceptibility Of Hiv-1-infectmentioning

confidence: 99%

Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity

Arias

Heyer

Bredow

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

145

159

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Significance HIV-1 viral protein U (Vpu) facilitates virus release from infected cells by down-regulating and degrading tetherin, a transmembrane protein upregulated by IFN that impedes the detachment of enveloped viruses from infected cells. Here we show that this activity of Vpu protects HIV-infected cells from antibodies that are capable of directing their elimination by antibody-dependent cell-mediated cytotoxicity. A direct implication of these observations is that tetherin serves as a link between innate and adaptive immunity to enhance the susceptibility of virus-infected cells to antibodies. Thus, the antiviral activity of tetherin may be much greater than previously appreciated based on its ability to inhibit virus release in cell culture assays.

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“…A number of studies have shown that casein kinase II phosphorylation of a pair of conserved serine residues (Ser-52 and Ser-56) in the cytoplasmic tail of Vpu recruits ␤-TrCP2, a component of the SKP1-CUL-F box E3 ubiquitin ligase complex, which leads to the down-regulation and degradation of tetherin (44, 46 -48). ␤-TrCP2-dependent degradation involves non-lysine ubiquitination of residues in the cytoplasmic domain of tetherin (49,50), which serves as a signal for HRS binding and ESCRT-mediated trafficking to lysosomal compartments (51). Vpu-mediated targeting of tetherin to lysosomes also requires Rab7A (52), a small GTPase essential for the maturation of late endosomes and lysosomal fusion.…”

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

243

250

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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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Serine-Threonine Ubiquitination Mediates Downregulation of BST-2/Tetherin and Relief of Restricted Virion Release by HIV-1 Vpu

Cited by 112 publications

References 46 publications

Ubiquitination of BST-2 Protein by HIV-1 Vpu Protein Does Not Require Lysine, Serine, or Threonine Residues within the BST-2 Cytoplasmic Domain

Ubiquitination of BST-2 Protein by HIV-1 Vpu Protein Does Not Require Lysine, Serine, or Threonine Residues within the BST-2 Cytoplasmic Domain

Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity

The Restriction Factors of Human Immunodeficiency Virus

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