The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry

Gordon-Alonso, Mónica; Rocha-Perugini, Vera; Álvarez, Susana; Moreno-Gonzalo, Olga; Ursa, Ángeles; López-Martín, Sara; Izquierdo-Useros, Nuria; Martínez-Picado, Javier; Muñoz‐Fernández, María Ángeles; Yáñez-Mó, Marı́a; Sánchez-Madrid, Francisco

doi:10.1091/mbc.e11-12-1003

Cited by 33 publications

(46 citation statements)

References 48 publications

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“…Furthermore, a spatiotemporal regulatory role for syntenin-1 in actin remodeling has also been documented in CD4 T cells during HIV-1 binding and entry (50). By single-cell force spectroscopy, we have here demonstrated that the interaction with syntenin-1 is strictly dependent on Thr residues in the cytoplasmic tail of ALCAM.…”

Section: Discussionsupporting

confidence: 52%

Syntenin-1 and Ezrin Proteins Link Activated Leukocyte Cell Adhesion Molecule to the Actin Cytoskeleton

Tudor

Riet

Eich

et al. 2014

Journal of Biological Chemistry

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Background:The activated leukocyte cell adhesion molecule (ALCAM) is involved in immune responses and cancer metastasis. Results: ALCAM is linked to the actin cytoskeleton through a supramolecular complex, including ezrin and syntenin-1. Conclusion: ALCAM supramolecular complex engaged to CD6 stabilizes the immunological synapse. Significance: Insights into the immunological synapse at the dendritic cell side contribute to clarify immune regulation mechanisms.

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Section: Discussionsupporting

confidence: 52%

Syntenin-1 and Ezrin Proteins Link Activated Leukocyte Cell Adhesion Molecule to the Actin Cytoskeleton

Tudor

Riet

Eich

et al. 2014

Journal of Biological Chemistry

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“…Moreover and considering resting lymphocytes, memory CD4+ T cells appear to be more susceptible to be infected by HIV-1 compared to naïve cells [19], [37]–[41]. Resting CD4+ T cells represent a major reservoir of HIV-1 [39], [40], being responsible for viremia when antiretroviral therapy is stopped [40].…”

Section: Resultsmentioning

confidence: 99%

Quantitative Analysis of the Processes and Signaling Events Involved in Early HIV-1 Infection of T Cells

2014

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Lymphocyte invasion by HIV-1 is a complex, highly regulated process involving many different types of molecules that is prompted by the virus's association with viral receptors located at the cell-surface membrane that culminates in the formation of a fusion pore through which the virus enters the cell. A great deal of work has been done to identify the key actors in the process and determine the regulatory interactions; however, there have been no reports to date of attempts being made to fully understand the system dynamics through a systemic, quantitative modeling approach. In this paper, we introduce a dynamic mathematical model that integrates the available information on the molecular events involved in lymphocyte invasion. Our model shows that moesin activation is induced by virus signaling, while filamin-A is mobilized by the receptor capping. Actin disaggregation from the cap is facilitated by cofilin. Cofilin is inactivated by HIV-1 signaling in activated lymphocytes, while in resting lymphocytes another signal is required to activate cofilin in the later stages in order to accelerate the decay of the aggregated actin as a restriction factor for the viral entry. Furthermore, stopping the activation signaling of moesin is sufficient to liberate the actin filaments from the cap. The model also shows the positive effect of gelsolin on actin capping by means of the nucleation effect. These findings allow us to propose novel approaches in the search for new therapeutic strategies. In particular, gelsolin inhibition is seen as a promising target for preventing HIV-1 entry into lymphocytes, due to its role in facilitating the capping needed for the invasion. Also it is shown that HIV-1 should overcome the cortical actin barrier during early infection and predicts the different susceptibility of CD4+ T cells to be infected in terms of actin cytoskeleton dynamics driven by associated cellular factors.

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“…The dense actin structure that favors CD4/CXCR4 clustering during attachment might subsequently act as a physical barrier that impairs introduction of the viral nucleocapsid. Therefore, a functional but loose actin cytoskeleton seems to be favorable for HIV-1 entry into the host cell (26,57). We have previously reported that silencing syntenin-1, a scaffold protein that binds to the cytoplasmic region of CD4, reduced F-actin polymerization in response to HIV-1 and this promoted HIV-1 entry (57).…”

Section: Discussionmentioning

confidence: 99%

“…Here we show that drebrin also plays a role in HIV-triggered actin polymerization. Reduction of the F-actin structure may render cells more permissive to subsequent HIV-1 nucleocapsid entry, accounting for the negative role of drebrin and syntenin-1 in the HIV-1 entry step (57). Although syntenin-1 silencing increases PIP-2 formation at Env-mediated contacts, drebrin does not.…”

Section: Discussionmentioning

confidence: 99%

Actin-binding Protein Drebrin Regulates HIV-1-triggered Actin Polymerization and Viral Infection

Gordon-Alonso

Rocha-Perugini

Álvarez

et al. 2013

Journal of Biological Chemistry

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Background: Drebrin binds to F-actin and CXCR4 in T cells. Thus, it is a potential candidate for the modulation of HIV-1 infection. Results: Drebrin and CXCR4 accumulate at viral attachment areas. Drebrin knockdown decreases F-actin polymerization, and increases local profilin accumulation and HIV-1 infection. Conclusion: Drebrin inhibits HIV-1 entry by stabilizing HIV-1-triggered F-actin polymerization. Significance: Modulation of actin dynamics differentially regulates each viral step for an effective viral infection. HIV-1 contact with target cells triggers F-actin rearrangements that are essential for several steps of the viral cycle. Successful HIV entry into CD4؉ T cells requires actin reorganization induced by the interaction of the cellular receptor/co-receptor complex CD4/CXCR4 with the viral envelope complex gp120/gp41 (Env).In this report, we analyze the role of the actin modulator drebrin in HIV-1 viral infection and cell to cell fusion. We show that drebrin associates with CXCR4 before and during HIV infection. Drebrin is actively recruited toward cellvirus and Env-driven cell to cell contacts. After viral internalization, drebrin clustering is retained in a fraction of the internalized particles. Through a combination of RNAi-based inhibition of endogenous drebrin and GFP-tagged expression of wild-type and mutant forms, we establish drebrin as a negative regulator of HIV entry and HIV-mediated cell fusion. Down-regulation of drebrin expression promotes HIV-1 entry, decreases F-actin polymerization, and enhances profilin local accumulation in response to HIV-1. These data underscore the negative role of drebrin in HIV infection by modulating viral entry, mainly through the control of actin cytoskeleton polymerization in response to HIV-1.Human immunodeficiency virus (HIV)-1 entry requires fusion between the viral envelope and the plasma membrane of the target cell (1). This process is mediated by the viral envelope glycoprotein complex gp120/gp41 (Env), 5 which interacts first with CD4 and then with a co-receptor, one of the chemokine receptors CCR5 or CXCR4 (2, 3).For the viral and cellular membranes to fuse, a critical number of gp120-CD4/coreceptor engagements are needed to establish an energetically productive fusion pore (4). HIV-1 can also be transmitted from infected to uninfected cells through cell to cell contacts, called virological synapses because of their similarities to the immunological synapse (5). As an example, CD4 and CXCR4 recruitment (6 -8) and local actin polymerization take place in both processes (6, 9 -11). Receptor clustering is regulated by two main factors: 1) insertion into specific membrane domains by lateral membrane receptor interactions (12) such as lipid rafts (13) or tetraspanin-enriched microdomains (14 -17); and 2) actin remodeling (6, 18 -20). This phenomenon is well illustrated by experiments in which HIV-1 contact induces CD4 and CXCR4 capping at the plasma membrane of target CD4 ϩ T lymphocytes (21,22). Receptor capping requires the formation of a subcortical...

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The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry

Cited by 33 publications

References 48 publications

Syntenin-1 and Ezrin Proteins Link Activated Leukocyte Cell Adhesion Molecule to the Actin Cytoskeleton

Syntenin-1 and Ezrin Proteins Link Activated Leukocyte Cell Adhesion Molecule to the Actin Cytoskeleton

Quantitative Analysis of the Processes and Signaling Events Involved in Early HIV-1 Infection of T Cells

Actin-binding Protein Drebrin Regulates HIV-1-triggered Actin Polymerization and Viral Infection

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