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, Jean K.; Douglas, Janet L.; Bai, Ying; Moses, Ashlee V.

doi:10.1074/jbc.m112.349928

Cited by 36 publications

(45 citation statements)

References 71 publications

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“…However, prolonged cell exposure to proteosomal inhibitors was shown to deplete the cellular pool of free ubiquitin, thus affecting not only the proteasomal, but also ubiquitindependent lysosomal degradation. These data therefore support the hypothesis that the Vpu-induced downregulation of BST-2 is at least in part ubiquitin-dependent [97,106].…”

Section: Intracellular Fate Of Bst-2 In the Presence Of Vpusupporting

confidence: 86%

Sites of Action of HIV-1 Vpu in BST-2/Tetherin Downregulation

Arias¹,

Iwabu²,

Tokunaga

2012

CHR

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The interferon-inducible host restriction factor bone marrow stromal antigen 2 (BST-2/tetherin) blocks the release of human immunodeficiency virus type 1 (HIV-1) by directly cross-linking virions to the membrane of infected cells. This antiviral effect is counteracted by the HIV-1 accessory protein viral protein U (Vpu) through mechanisms that remain unclear. Accumulating evidence suggests that Vpu antagonizes BST-2 by removing it from the plasma membrane; however, neither the cellular sites of interaction nor the effector mechanisms that result in the downregulation of BST-2 cell-surface expression have been fully determined. Based on current evidence regarding the subcellular localization of Vpu and BST-2 and the latter's trafficking defects induced by their interaction, three models have been proposed. In the first, Vpu is hypothesized to block the traffic of newly synthesized BST-2 towards the cell surface by retaining it in the biosynthetic/secretory compartment. The second model suggests that Vpu sequesters BST-2 within intracellular compartments corresponding to recycling endosomes and the trans-Golgi network by blocking its recycling after endocytosis. In the third model, we and others have proposed that Vpu directly internalizes BST-2 from the plasma membrane and induces its enhanced endolysosomal trafficking and degradation. As for its intracellular fate, the viral antagonism of BST-2 is likely dependent on the intracellular sequestration, or the proteasomal/lysosomal degradation of the restriction factor. This review summarizes the current advances in our understanding of the cellular pathways and sites of action of Vpu in the downregulation of cell-surface BST-2.

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Section: Intracellular Fate Of Bst-2 In the Presence Of Vpusupporting

confidence: 86%

Sites of Action of HIV-1 Vpu in BST-2/Tetherin Downregulation

Arias¹,

Iwabu²,

Tokunaga

2012

CHR

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“…Yet another viral protein, the HIV protein, VPU, utilizes the SCF β-TrCP E3 ligase to modify two substrates, tetherin and CD4, by utilizing lysine, serine, and threonine [215, 216]. Additional evidence obtained investigating the ubiquitination of tetherin by SCF β-TrCP suggested that tyrosine residues in the cytoplasmic domain, or the free amino group in the N-terminus, might be targeted [217]. Since the exact nature of polyubiquitin chains in ERAD substrates is rarely investigated, it is possible that these phenomena are actually quite common.…”

Section: Variations On a Themementioning

confidence: 99%

The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation

Preston

Brodsky

2017

Biochemical Journal

133

104

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The endoplasmic reticulum (ER) serves as a warehouse for factors that augment and control the biogenesis of nascent proteins entering the secretory pathway. In turn, this compartment also harbors the machinery that responds to the presence of misfolded proteins by targeting them for proteolysis via a process known as ER-associated degradation (ERAD). During ERAD, substrates are selected, modified with ubiquitin, removed from the ER, and then degraded by the cytoplasmic 26S proteasome. While integral membrane proteins can directly access the ubiquitination machinery that resides in the cytoplasm or on the cytoplasmic face of the ER membrane, soluble ERAD substrates within the lumen must be retrotranslocated from this compartment. In either case, nearly all ERAD substrates are tagged with a polyubiquitin chain, a modification that represents a commitment step to degrade aberrant proteins. However, increasing evidence indicates that the polyubiquitin chain on ERAD substrates can be further modified, serves to recruit ERAD-requiring factors, and may regulate the ERAD machinery. Amino acid side chains other than lysine on ERAD substrates can also be modified with ubiquitin, and post-translational modifications that affect substrate ubiquitination have been observed. Here, we summarize these data and provide an overview of questions driving this field of research.

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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.

150

161

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

Cited by 36 publications

References 71 publications

Sites of Action of HIV-1 Vpu in BST-2/Tetherin Downregulation

Sites of Action of HIV-1 Vpu in BST-2/Tetherin Downregulation

The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation

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

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