LC3C Contributes to Vpu-Mediated Antagonism of BST2/Tetherin Restriction on HIV-1 Release through a Non-canonical Autophagy Pathway

Madjo, Ursula; Leymarie, Olivier; Frémont, Stéphane; Kuster, Aurelia; Nehlich, Melanie; Gallois-Montbrun, Sarah; Janvier, Katy; Berlioz‐Torrent, Clarisse

doi:10.1016/j.celrep.2016.10.045

Cited by 38 publications

(54 citation statements)

References 32 publications

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“…We also noted that Vpu expression levels were similar in WT, ELV, and 2.6 HIV-1-infected MDMs and that mutation of the A 14 and W 22 residues in Vpu led to a protein with a higher apparent molecular weight and reduced expression ( Fig. 5D), as previously shown (42,47). In addition, we observed that mutated Vpu proteins are less efficient in downregulating BST2 than WT Vpu (Fig.…”

Section: Role Of Vpu In Hiv Sequestration In Macrophagessupporting

confidence: 84%

“…We recently described that Vpu favors the displacement of BST2 from viral budding sites through the recruitment of the microtubule-associated protein 1 light chain 3 (LC3)-associated phagocytosis (LAP) machinery, involving the LC3C protein. Indeed, Vpu interacts via its L 63 VEM 66 motif, present on the second alpha helix of its cytoplasmic tail, with LC3C to promote the phagocytosis of BST2 (47). Interestingly, the Vpu E 59 XXXLV 64 dileucine-like motif, which overlaps the L 63 VEM 66 motif, was also shown to be important for efficient HIV-1 release.…”

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confidence: 99%

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Contribution of the Cytoplasmic Determinants of Vpu to the Expansion of Virus-Containing Compartments in HIV-1-Infected Macrophages

Leymarie

Lepont

Versapuech

et al. 2019

J Virol

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HIV-1 infection of macrophages leads to the sequestration of newly formed viruses in intracellular plasma membrane-connected structures termed virus-containing compartments (VCCs), where virions remain infectious and hidden from immune surveillance. The cellular restriction factor bone marrow stromal cell antigen 2 (BST2), which prevents HIV-1 dissemination by tethering budding viral particles at the plasma membrane, can be found in VCCs. The HIV-1 accessory protein Vpu counteracts the restriction factor BST2 by downregulating its expression and removing it from viral budding sites. Numerous studies described these Vpu countermeasures in CD4 ϩ T cells or model cell lines, but the interplay between Vpu and BST2 in VCC formation and HIV-1 production in macrophages is less explored. Here, we show that Vpu expression in HIV-1-infected macrophages enhances viral release. This effect is related to Vpu's ability to circumvent BST2 antiviral activity. We show that in absence of Vpu, BST2 is enriched in VCCs and colocalizes with capsid p24, whereas Vpu expression significantly reduces the presence of BST2 in these compartments. Furthermore, our data reveal that BST2 is dispensable for the formation of VCCs and that Vpu expression impacts the volume of these compartments. This Vpu activity partly depends on BST2 expression and requires the integrity of the Vpu transmembrane domain, the dileucine-like motif E 59 XXXLV 64 and phosphoserines 52 and 56 of Vpu. Altogether, these results highlight that Vpu controls the volume of VCCs and promotes HIV-1 release from infected macrophages. IMPORTANCE HIV-1 infection of macrophages leads to the sequestration of newly formed viruses in virus-containing compartments (VCCs), where virions remain infectious and hidden from immune surveillance. The restriction factor BST2, which prevents HIV-1 dissemination by tethering budding viral particles, can be found in VCCs. The HIV-1 Vpu protein counteracts BST2. This study explores the interplay between Vpu and BST2 in the viral protein functions on HIV-1 release and viral particle sequestration in VCCs in macrophages. The results show that Vpu controls the volume of VCCs and favors viral particle release. These Vpu functions partly depend on Vpu's ability to antagonize BST2. This study highlights that the transmembrane domain of Vpu and two motifs of the Vpu cytoplasmic domain are required for these functions. These motifs were notably involved in the control of the volume of VCCs by Vpu but were dispensable for the prevention of the specific accumulation of BST2 in these structures.

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Section: Role Of Vpu In Hiv Sequestration In Macrophagessupporting

confidence: 84%

mentioning

confidence: 99%

Contribution of the Cytoplasmic Determinants of Vpu to the Expansion of Virus-Containing Compartments in HIV-1-Infected Macrophages

Leymarie

Lepont

Versapuech

et al. 2019

J Virol

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“…RNA extractions and RT-qPCR analyses were performed as described previously (Madjo et al, 2016). RNAs that had been extracted using the QIAGEN RNeasy Mini kit and treated with DNAse (Qiagen, RNAse-free DNase set) were reverse transcribed using the High Capacity Reverse Transcription kit (Applied Biosystem) and quantified using real-time PCR using the Roche LightCycler 480 SYBR Green 1 Master kit (Roche Diagnostics) and specific primers.…”

Section: Methodsmentioning

confidence: 99%

Characterization of E3 ligases involved in lysosomal sorting of the HIV-1 restriction factor BST2

Roy

Pacini

Berlioz‐Torrent

et al. 2017

Journal of Cell Science

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The cellular protein BST2 (also known as tetherin) acts as a major intrinsic antiviral protein that prevents the release of enveloped viruses by trapping nascent viral particles at the surface of infected cells. Viruses have evolved specific strategies to displace BST2 from viral budding sites in order to promote virus egress. In HIV-1, the accessory protein Vpu counters BST2 antiviral activity and promotes sorting of BST2 for lysosomal degradation. Vpu increases polyubiquitylation of BST2, a post-translation modification required for Vpu-induced BST2 downregulation, through recruitment of the E3 ligase complex SCF adaptors β-TrCP1 and β-TrCP2 (two isoforms encoded by BTRC and FBXW11, respectively). Herein, we further investigate the role of the ubiquitylation machinery in the lysosomal sorting of BST2. Using a small siRNA screen, we highlighted two additional regulators of BST2 constitutive ubiquitylation and sorting to the lysosomes: the E3 ubiquitin ligases NEDD4 and MARCH8. Interestingly, Vpu does not hijack the cellular machinery that is constitutively involved in BST2 ubiquitylation to sort BST2 for degradation in the lysosomes but instead promotes the recognition of BST2 by β-TrCP proteins. Altogether, our results provide further understanding of the mechanisms underlying BST2 turnover in cells.

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“…Recently, it has been reported that Vpu may hijack the function of the host actin cross-linking regulator filamin A (FLNa) during its quest of BST-2 modulation (Dotson et al 2016). Vpu may also exploit an LC3-associated noncanonical autophagy pathway to restrict BST-2 (Madjo et al 2016). The refinement of current models, together with the discovery of additional host and/or intraviral factors involved, will ultimately form a complete and accurate picture of Vpu-mediated BST-2 antagonism.…”

Section: Vpu-mediated Antagonism Of Bst-2mentioning

confidence: 99%

Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

Torres

2018

Subcellular Biochemistry

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Viroporins are short polypeptides encoded by viruses. These small membrane proteins assemble into oligomers that can permeabilize cellular lipid bilayers, disrupting the physiology of the host to the advantage of the virus. Consequently, efforts during the last few decades have been focused towards the discovery of viroporin channel inhibitors, but in general these have not been successful to produce licensed drugs. Viroporins are also involved in viral pathogenesis by engaging in critical interactions with viral proteins, or disrupting normal host cellular pathways through coordinated interactions with host proteins. These protein-protein interactions (PPIs) may become alternative attractive drug targets for the development of antivirals. In this sense, while thus far most antiviral molecules have targeted viral proteins, focus is moving towards targeting host proteins that are essential for virus replication. In principle, this largely would overcome the problem of resistance, with the possibility of using repositioned existing drugs. The precise role of these PPIs, their strain- and host- specificities, and the structural determination of the complexes involved, are areas that will keep the fields of virology and structural biology occupied for years to come. In the present review, we provide an update of the efforts in the characterization of the main PPIs for most viroporins, as well as the role of viroporins in these PPIs interactions.

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LC3C Contributes to Vpu-Mediated Antagonism of BST2/Tetherin Restriction on HIV-1 Release through a Non-canonical Autophagy Pathway

Cited by 38 publications

References 32 publications

Contribution of the Cytoplasmic Determinants of Vpu to the Expansion of Virus-Containing Compartments in HIV-1-Infected Macrophages

Contribution of the Cytoplasmic Determinants of Vpu to the Expansion of Virus-Containing Compartments in HIV-1-Infected Macrophages

Characterization of E3 ligases involved in lysosomal sorting of the HIV-1 restriction factor BST2

Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

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