EWI-2 Association with α-Actinin Regulates T Cell Immune Synapses and HIV Viral Infection

Gordon-Alonso, Mónica; Sala-Valdés, Mónica; Rocha-Perugini, Vera; Pérez-Hernández, Daniel; López-Martín, Sara; Ursa, Ángeles; Álvarez, Susana; Kolesnikova, Tatiana V.; Vázquez, Jesús; Sánchez-Madrid, Francisco; Yáñez-Mó, Marı́a

doi:10.4049/jimmunol.1103708

Cited by 46 publications

(51 citation statements)

References 71 publications

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“…In accordance, activation of the actin-severing protein cofilin has been associated with enhanced HIV entry (26). Moreover, both removal of the bundling activity or siRNA knockdown of ␣-actinin, an actin microfilament cross-linker, increase HIV-1 infection (30). In addition, knockdown of proteins that link the actin cytoskeleton with the inner leaflet of the plasma membrane, such as talin and vinculin, have also been related with higher HIV-1 infection (31).…”

mentioning

confidence: 67%

“…Clustering of CD4/CXCR4 has been suggested to depend on their incorporation into tetra-spanin-enriched microdomains (14 -16, 62) and to require cholesterol-enriched domains (46,54,55), attesting the importance of membrane microdomains for HIV-1 entry. Tetraspanin-enriched microdomains are linked to actin cytoskeleton through actin-binding proteins ERMs and ␣-actinin (30,63). ERMs and filamin-A, another actin-binding protein, are known to facilitate CD4/CXCR4 clustering during HIV-1 attachment and promote viral infection (18,20).…”

Section: Discussionmentioning

confidence: 99%

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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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confidence: 67%

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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“…Immunoglobulin superfamily (IgSF) proteins such as EWI-2, EWI-F, ICAM-1, or VCAM-1, which are direct partners of tetraspanins CD9 and CD81, also present binding sites for actin-linking ERM proteins (33, 34). A proteomic study in human primary lymphoblasts and their derived EVs identified the association of CD81 with a large number of interacting partners, including alpha-actinin (35, 36). In the activation and adhesion of T cells, an inducible association of CD82 with the cytoskeletal matrix has been observed, so that CD82 induces spreading and development of membrane extensions, involving actin polymerization and contributing to T cell activation via their cytoplasmic domain (37).…”

Section: Tetraspanin Structure: the Key For Their Involvement In So Mmentioning

confidence: 99%

Tetraspanins in Extracellular Vesicle Formation and Function

Andreu

Yáñez-Mó²

2014

Front. Immunol.

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Extracellular vesicles (EVs) represent a novel mechanism of intercellular communication as vehicles for intercellular transfer of functional membrane and cytosolic proteins, lipids, and RNAs. Microvesicles, ectosomes, shedding vesicles, microparticles, and exosomes are the most common terms to refer to the different kinds of EVs based on their origin, composition, size, and density. Exosomes have an endosomal origin and are released by many different cell types, participating in different physiological and/or pathological processes. Depending on their origin, they can alter the fate of recipient cells according to the information transferred. In the last two decades, EVs have become the focus of many studies because of their putative use as non-invasive biomarkers and their potential in bioengineering and clinical applications. In order to exploit this ability of EVs many aspects of their biology should be deciphered. Here, we review the mechanisms involved in EV biogenesis, assembly, recruitment of selected proteins, and genetic material as well as the uptake mechanisms by target cells in an effort to understand EV functions and their utility in clinical applications. In these contexts, the role of proteins from the tetraspanin superfamily, which are among the most abundant membrane proteins of EVs, will be highlighted.

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“…B cells (Raji or Hom2) were loaded with the CMAC tracker and loaded with SEE (0.5 to 1 g/ml) or HA peptide (100 to 200 g/ml), as appropriate (41). J77 or CH7C17 T cells were mixed with Raji or Hom2 B cells (1:1), centrifuged at low speed to favor conjugate formation, and incubated at 37°C for the indicated periods of time.…”

Section: Methodsmentioning

confidence: 99%

CD81 Controls Sustained T Cell Activation Signaling and Defines the Maturation Stages of Cognate Immunological Synapses

Rocha-Perugini

Zamai

González-Granado

et al. 2013

Molecular and Cellular Biology

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In this study, we investigated the dynamics of the molecular interactions of tetraspanin CD81 in T lymphocytes, and we show that CD81 controls the organization of the immune synapse (IS) and T cell activation. Using quantitative microscopy, including fluorescence recovery after photobleaching (FRAP), phasor fluorescence lifetime imaging microscopy-Föster resonance energy transfer (phasorFLIM-FRET), and total internal reflection fluorescence microscopy (TIRFM), we demonstrate that CD81 interacts with ICAM-1 and CD3 during conjugation between T cells and antigen-presenting cells (APCs). CD81 and ICAM-1 exhibit distinct mobilities in central and peripheral areas of early and late T cell-APC contacts. Moreover, CD81-ICAM-1 and CD81-CD3 dynamic interactions increase over the time course of IS formation, as these molecules redistribute throughout the contact area. Therefore, CD81 associations unexpectedly define novel sequential steps of IS maturation. Our results indicate that CD81 controls the temporal progression of the IS and the permanence of CD3 in the membrane contact area, contributing to sustained T cell receptor (TCR)-CD3-mediated signaling. Accordingly, we find that CD81 is required for proper T cell activation, regulating CD3, ZAP-70, LAT, and extracellular signal-regulated kinase (ERK) phosphorylation; CD69 surface expression; and interleukin-2 (IL-2) secretion. Our data demonstrate the important role of CD81 in the molecular organization and dynamics of the IS architecture that sets the signaling threshold in T cell activation. The interaction between T lymphocytes and antigen-presenting cells (APCs) is essential for the initiation of the immune response. The dynamic structure formed at cell-to-cell contacts between T cells and APCs, called the immune synapse (IS), is characterized by controlled recruitment of membrane receptors to specific subcellular sites (1). Upon activation by an APC, T cell molecules involved in the IS redistribute in highly organized structures at the T cell-APC contact (2). The T cell receptor (TCR) and associated molecules concatenate into the central area (central supramolecular activation cluster [cSMAC]), whereas adhesion receptors rearrange in a surrounding external ring called the peripheral supramolecular activation cluster (pSMAC) (3). During IS formation, preclustered TCR "protein islands" converge into larger aggregates that translocate toward the cSMAC (4, 5), from where they are internalized and degraded (6). The balance between the generation and degradation of TCR microclusters is critical for sustained T cell activation (5, 7) and is modulated by ligand mobility (8). However, the mechanisms regulating protein receptor movement and the basis for IS molecular segregation are still poorly understood.A plethora of molecules are translocated to the IS during T cell activation (9). These include the tetraspanins CD81 (10) and CD82 (11), which are known to associate with several IS components such as major histocompatibility complex class II (MHCII) molecules, CD4, and LF...

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EWI-2 Association with α-Actinin Regulates T Cell Immune Synapses and HIV Viral Infection

Cited by 46 publications

References 71 publications

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

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

Tetraspanins in Extracellular Vesicle Formation and Function

CD81 Controls Sustained T Cell Activation Signaling and Defines the Maturation Stages of Cognate Immunological Synapses

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