Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes

Barrero-Villar, Marta; Cabrero, José Román; Gordon-Alonso, Mónica; Barroso-González, Jonathan; Álvarez-Losada, Susana; Muñoz‐Fernández, María Ángeles; Sánchez-Madrid, Francisco; Valenzuela-Fernández, Agustı́n

doi:10.1242/jcs.035873

Cited by 115 publications

(239 citation statements)

References 49 publications

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“…CXCR4 and CCR5 are present as homodimers and heterodimers at the plasma membrane (18)(19)(20). In addition, gp120-mediated CD4/CXCR4 and CD4/CCR5 association and clustering is reported (21)(22)(23). Nonetheless, little is known of how CCR5 expression influences the CD4/CXCR4 interaction, or of the molecular basis that underlies the differences in X4 strains infection relative to CCR5 levels at the cell surface.…”

mentioning

confidence: 99%

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

Martínez-Muñoz

Barroso

Dyrhaug

et al. 2014

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

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CCR5 and CXCR4, the respective cell surface coreceptors of R5 and X4 HIV-1 strains, both form heterodimers with CD4, the principal HIV-1 receptor. Using several resonance energy transfer techniques, we determined that CD4, CXCR4, and CCR5 formed heterotrimers, and that CCR5 coexpression altered the conformation of both CXCR4/CXCR4 homodimers and CD4/CXCR4 heterodimers. As a result, binding of the HIV-1 envelope protein gp120 IIIB to the CD4/CXCR4/CCR5 heterooligomer was negligible, and the gp120-induced cytoskeletal rearrangements necessary for HIV-1 entry were prevented. CCR5 reduced HIV-1 envelope-induced CD4/ CXCR4-mediated cell-cell fusion. In nucleofected Jurkat CD4 cells and primary human CD4 + T cells, CCR5 expression led to a reduction in X4 HIV-1 infectivity. These findings can help to understand why X4 HIV-1 strains infection affect T-cell types differently during AIDS development and indicate that receptor oligomerization might be a target for previously unidentified therapeutic approaches for AIDS intervention.chemokine receptors | oligomer formation | FRET/BRET F or HIV-1 to enter a target cell, the viral envelope glycoprotein gp120 must interact with a set of cell surface molecules that include the primary receptor, CD4 (1), and a chemokine receptor (CCR5 or CXCR4) that acts as a coreceptor (2, 3). These molecules form CD4/chemokine receptor complexes, as deduced from coprecipitation data for CXCR4 or CCR5 with CD4 (4-8).Most HIV-1 variants isolated from newly infected individuals use CCR5 and CD4 to enter host cells; these M-tropic R5 strains are predominant in acute and asymptomatic phases of HIV infection. CD4 + T helper type 1 (Th1) cells, which express high CCR5 levels (9, 10), are implicated in maintaining asymptomatic status (11, 12). The "viral shift" from R5 to T-tropic X4 HIV-1 strains correlates with AIDS progression (13,14). X4 strains infect mainly CD4 + Th2 cells, which express little CCR5 and whose CXCR4 levels resemble those of Th1 cells (15,16), which suggests that cell susceptibility to HIV-1 infection depends on the CD4/coreceptor ratio and on receptor levels during cell activation and/or differentiation (17). CXCR4 and CCR5 are present as homodimers and heterodimers at the plasma membrane (18)(19)(20). In addition, gp120-mediated CD4/CXCR4 and CD4/CCR5 association and clustering is reported (21-23). Nonetheless, little is known of how CCR5 expression influences the CD4/CXCR4 interaction, or of the molecular basis that underlies the differences in X4 strains infection relative to CCR5 levels at the cell surface.Here, we identify CD4/CXCR4/CCR5 oligomers at the cell membrane, even in the absence of ligands. CCR5 expression in these complexes modifies the heterodimeric CD4/CXCR4 conformation and blocks gp120 IIIB binding, without altering binding of the CXCR4 ligand CXCL12 and its subsequent signaling. gp120 IIIB -triggered LIMK1 activation, cofilin dephosphorylation, and the actin cytoskeleton rearrangement necessary for cell-cell fusion were impeded in CD4/CXCR4/CCR5-expressing c...

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confidence: 99%

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

Martínez-Muñoz

Barroso

Dyrhaug

et al. 2014

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

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“…Three types of actin-interacting proteins were shown to play critical roles in this process: filamin, ERM and cofilin [47]. Among ERMs, Barrero-Villar et al [48] found that moesin was phosphorylated after HIV-1 interaction and drove redistribution and clustering of CD4 and of CXCR4, through promotion of F-actin redistribution. Another study [49] showed, using an ezrin dominant negative mutant and knockdowns of ERM, that ERMs were involved in the cell infection by X4-tropic HIV-1 strain, a strain that requires the presence of the CXCR4 receptor for infection [49].…”

Section: Virus Entry In Cells-mentioning

confidence: 99%

Model membranes to shed light on the biochemical and physical properties of ezrin/radixin/moesin

2013

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Ezrin, radixin and moesin (ERM) proteins are now more and more recognized to play a key role in a large number of important physiological processes such as morphogenesis, cancer metastasis and virus infection. Several recent reviews extensively discuss their biological functions [1][2][3][4]. In this review, we will first remind the main features of this family of proteins, which are now known as linkers and regulators of the plasma membrane/cytoskeleton linkage. We will then briefly review their implication in pathological processes such as cancer and viral infection. In a second part, we will focus on biochemical and biophysical approaches to study ERM interaction with lipid membranes and conformational change in well-defined environments. In vitro studies using biomimetic lipid membranes, especially large unilamellar vesicles (LUVs), giant unilamellar vesicles (GUVs) and supported lipid bilayers (SLBs) and recombinant proteins help to understand the molecular mechanism of conformational activation of ERM proteins. These tools are aimed to decorticate the different steps of the interaction, to simplify the experiments performed in vivo in much more complex biological environments. KeywordsEzrin; radixin and moesin; biomimetic membranes; phosphoinositol (4,5)-bisphosphate (PIP 2 ); large unilamellar vesicles; supported lipid bilayers; giant unilamelar vesicles Corresponding author: Catherine Picart, CNRS UMR 5628 (LMGP), Grenoble Institute of Technology and CNRS, 3 parvis Louis Néel, F-38016 Grenoble Cedex, France. Europe PMC Funders GroupAuthor Manuscript Biochimie. Author manuscript; available in PMC 2014 July 28. Published in final edited form as:Biochimie. 2013 January ; 95(1): 3-11. doi:10.1016/j.biochi.2012.09.033. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts Biological importance of Ezrin, Radixin and Moesin General overview of ERM proteins (Ezrin, Radixin, Moesin)ERM proteins are localized at the plasma membrane in actin-rich surface structures (Fig 1) [5], such as microvilli, membrane ruffles, and lamellipodia in gut cells, lymphocytes, hepatocytes, spermatozoids, fibroblasts and in a variety of other cell types [5][6][7][8][9]. They are involved in various physiological processes including establishment of cell polarity, cell motility and cell signaling [10]. They act as linkers between the plasma membrane and the cortical actin cytoskeleton. From a structural point of view, ERMs are constituted of 3 domains : a membrane binding domain, also known as FERM (for band 4.1 protein, ezrin, radixin and moesin), and intermediary region and a actin binding domain called C-ERMAD (for C-terminal ERM-association domain) (Fig 2A).The FERM domain, constituted of ~300 amino acids, is characteristic of the proteins of the band 4.1 superfamily. These proteins also present other types of domains, including PDZ, tyrosine phosphatase, SH2-like, tyrosine kinase, kinase-like, myosin head, and PH domains [11]. In ERM proteins, the FERM domain is followed by a long α-helical region, whi...

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“…Concomitantly, there is a local activation and accumulation of moesin and ezrin together with filamentous actin (F-actin), the actin-binding protein filamin and the severing protein cofilin to the synapse. Small interfering RNA-mediated knockdown of ERMs strongly diminishes the ability of HIV-1 to enter and infect cells [53,54] and prevents the redistribution of CD4 and CXCR4 into the synapse [53] . CD4-CXCR4 clustering depends on the actin cytoskeleton, suggesting that ERMs facilitate virological synapse formation by anchoring actin filaments.…”

Section: The Role Of Erms In Retroviral and Bacterial Infectionsmentioning

confidence: 99%

Ezrin, Radixin and Moesin: Minor Molecule with Major Impact: A Review

Agarwal¹

2013

IOSR-JDMS

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Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes

Cited by 115 publications

References 49 publications

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

Model membranes to shed light on the biochemical and physical properties of ezrin/radixin/moesin

Ezrin, Radixin and Moesin: Minor Molecule with Major Impact: A Review

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Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes

Cited by 115 publications

References 49 publications

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIBbinding to the cell surface

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIBbinding to the cell surface

Model membranes to shed light on the biochemical and physical properties of ezrin/radixin/moesin

Ezrin, Radixin and Moesin: Minor Molecule with Major Impact: A Review

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CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120_IIIBbinding to the cell surface