Engagement of CD81 induces ezrin tyrosine phosphorylation and its cellular redistribution with filamentous actin

Coffey, Greg; Rajapaksa, Ranjani; Liu, Raymond; Sharpe, Orr; Kuo, Chiung-Chi; Krauss, Sharon Wald; Sagi, Yoav; Davis, R. Eric; Staudt, Louis M.; Sharman, Jeff P.; Robinson, William H.; Levy, Shoshana

doi:10.1242/jcs.045658

Cited by 53 publications

(72 citation statements)

References 53 publications

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“…Although we cannot rule out a functionally relevant transient or weak interaction between CD37 and b 2 integrin, we argue that the most likely model is that CD37 facilitates communication between b 2 integrins and the cytoskeleton. This model is consistent with several reports that tetraspanins modulate the activity of the cytoskeleton-regulating Rho GTPases (44,51,(59)(60)(61)(62), and interact with and regulate the activity of Ezrin-radixin-moesin proteins that can control cytoskeletal rearrangement through the Rho pathway (63,64). Thus, the impairment in the ability of CD37 2/2 neutrophils to bind stably to the vascular endothelium can be explained first by a defect in cytoskeletal rearrangement (Fig.…”

Section: Discussionsupporting

confidence: 91%

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Wee

Schulze

Jones

et al. 2015

The Journal of Immunology

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Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin–dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1–adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.

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Section: Discussionsupporting

confidence: 91%

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Wee

Schulze

Jones

et al. 2015

The Journal of Immunology

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“…Thus, while the relative exclusion of CD81 renders virions more infectious, it is independent from the ability of Nef to increase virus infectivity. Based on the CD81-Ezrin interaction (77,78), the differential incorporation of CD81 into virions might be a consequence of the exclusion of Ezrin from WT virions (see below). ALG-2 was also suspected to restrict virus infectivity, based on its relative enrichment in the poorly infectious nef-deleted virions.…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Analysis of HIV-1 Particles Reveals a Role for Ezrin and EHD4 in the Nef-Dependent Increase of Virus Infectivity

Brégnard

Zamborlini

Leduc

et al. 2013

J Virol

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gNef is a human immunodeficiency virus type 1 (HIV-1) auxiliary protein that plays an important role in virus replication and the onset of acquired immunodeficiency. Although known functions of Nef might explain its contribution to HIV-1-associated pathogenesis, how Nef increases virus infectivity is still an open question. In vitro, Nef-deleted viruses have a defect that prevents efficient completion of early steps of replication. We have previously shown that this restriction is not due to the absence of Nef in viral particles. Rather, a loss of function in virus-producing cells accounts for the lower infectivity of nef-deleted viruses compared to wild-type (WT) viruses. Here we used DiGE and iTRAQ to identify differences between the proteomes of WT and nef-deleted viruses. We observe that glucosidase II is enriched in WT virions, whereas Ezrin, ALG-2, CD81, and EHD4 are enriched in nef-deleted virions. Functional analysis shows that glucosidase II, ALG-2, and CD81 have no or only Nef-independent effect on infectivity. In contrast, Ezrin and EHD4 are involved in the ability of Nef to increase virus infectivity (referred to thereafter as Nef potency). Indeed, simultaneous Ezrin and EHD4 depletion in SupT1 and 293T virus-producing cells result in an ϳ30 and ϳ70% decrease of Nef potency, respectively. Finally, while Ezrin behaves as an inhibitory factor counteracted by Nef, EHD4 should be considered as a cofactors required by Nef to increase virus infectivity.

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“…CD81, a four transmembrane protein with short cytoplasmic N-and C-terminal domains lacks tyrosine activation motifs (46). Nevertheless, the C-terminal domain of CD81 was shown to associate directly with ezrin-radixin-moesin (ERM) proteins (47) and to modulate their activity (48). ERM proteins enable bridging between membrane proteins and the actin cytoskeleton and in doing so facilitate membrane reorganization (reviewed in ref.…”

Section: Kinetics Of Early Signaling Events In T-cell Activation Depementioning

confidence: 99%

Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81

Sagi¹,

Landrigan

Levy³

et al. 2012

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

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Cluster of differentiation 81 (CD81) is a widely expressed tetraspanin molecule that physically associates with CD4 and CD8 on the surface of human T cells. Coengagement of CD81 and CD3 results in the activation and proliferation of T cells. CD81 also costimulated mouse T cells that lack CD28, suggesting either a redundant or a different mechanism of action. Here we show that CD81 and CD28 have a preference for different subsets of T cells: Primary human naïve T cells are better costimulated by CD81, whereas the memory T-cell subsets and Tregs are better costimulated by CD28. The more efficient activation of naïve T cells by CD81 was due to prolonged signal transduction compared with that by CD28. We found that IL-6 played a role in the activation of the naïve T-cell subset by CD81. Combined costimulation through both CD28 and CD81 resulted in an additive effect on Tcell activation. Thus, these two costimulatory molecules complement each other both in the strength of signal transduction and in T-cell subset inclusions. Costimulation via CD81 might be useful for expansion of T cells for adoptive immunotherapy to allow the inclusion of naïve T cells with their broad repertoire.

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Engagement of CD81 induces ezrin tyrosine phosphorylation and its cellular redistribution with filamentous actin

Cited by 53 publications

References 53 publications

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Comparative Proteomic Analysis of HIV-1 Particles Reveals a Role for Ezrin and EHD4 in the Nef-Dependent Increase of Virus Infectivity

Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81

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