Ezrin and Moesin Are Required for Efficient T Cell Adhesion and Homing to Lymphoid Organs

Chen, Emily J. H.; Shaffer, Meredith H.; Williamson, Edward K.; Huang, Yanping; Burkhardt, Janis K.

doi:10.1371/journal.pone.0052368

Cited by 27 publications

(31 citation statements)

References 75 publications

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“…We recently investigated chemotaxis, adhesion, and homing of murine T-lymphoblasts lacking ezrin and with markedly reduced moesin expression (Chen et al, 2013). In agreement with this work on naive human T cells, in vitro chemotaxis to CCL19 of these T-lymphoblasts deficient in ERM proteins through 3 μm pores was reduced by 20–50%.…”

Section: Discussionmentioning

confidence: 99%

“…In line with these findings, naïve T cells derived from mice lacking moesin show reduced in vitro chemotaxis to CXCL12 and CCL21 (Hirata et al, 2012). Moreover murine T-lymphoblasts lacking ezrin and with strongly reduced moesin expression chemotax less efficiently in response to CCL19 than WT cells through 3 μm pores in transwell assays (Chen et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

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Ezrin/Radixin/Moesin Proteins and Flotillins Cooperate to Promote Uropod Formation in T Cells

Martinelli¹,

Chen²,

Clarke³

et al. 2013

Front. Immunol.

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T cell uropods are enriched in specific proteins including adhesion receptors such as P-selectin glycoprotein ligand-1 (PSGL-1), lipid raft-associated proteins such as flotillins and ezrin/radixin/moesin (ERM) proteins which associate with cholesterol-rich raft domains and anchor adhesion receptors to the actin cytoskeleton. Using dominant mutants and siRNA technology we have tested the interactions among these proteins and their role in shaping the T cell uropod. Expression of wild type (WT) ezrin-EGFP failed to affect the morphology of human T cells or chemokine-induced uropod recruitment of PSGL-1 and flotillin-1 and -2. In contrast, expression of constitutively active T567D ezrin-EGFP induced a motile, polarized phenotype in some of the transfected T cells, even in the absence of chemokine. These cells featured F-actin-rich ruffles in the front and uropod enrichment of PSGL-1 and flotillins. T567D ezrin-EGFP was itself strongly enriched in the rear of the polarized T cells. Uropod formation induced by T567D ezrin-EGFP was actin-dependent as it was attenuated by inhibition of Rho-kinase or myosin II, and abolished by disruption of actin filaments. While expression of constitutively active ezrin enhanced cell polarity, expression of a dominant-negative deletion mutant of ezrin, 1–310 ezrin-EGFP, markedly reduced uropod formation induced by the chemokine SDF-1, T cell front-tail polarity, and capping of PSGL-1 and flotillins. Transfection of T cells with WT or T567D ezrin did not affect chemokine-mediated chemotaxis whereas 1–310 ezrin significantly impaired spontaneous 2D migration and chemotaxis. siRNA-mediated downregulation of flotillins in murine T cells attenuated moesin capping and uropod formation, indicating that ERM proteins and flotillins cooperate in uropod formation. In summary, our results indicate that activated ERM proteins function together with flotillins to promote efficient chemotaxis of T cells by structuring the uropod of migrating T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ezrin/Radixin/Moesin Proteins and Flotillins Cooperate to Promote Uropod Formation in T Cells

Martinelli¹,

Chen²,

Clarke³

et al. 2013

Front. Immunol.

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“…Our expectation is that absence of ezrin will lead to reduced in vivo homing. This is based on the demonstration that mice lacking ERM proteins in mature T cells display decreased homing to lymphoid organs (49), and that transgenic mice expressing a constitutively active mutant of ezrin in T cells have defects in transendothelial T cell migration due to increase in membrane tension (50). We have demonstrated that treatment of naïve B cells with different stimuli such as antigen, chemokines, LPS and CD40 ligand results in dephosphorylation of T567 in ezrin, whereas phosphorylation at Y353 is only induced upon BCR crosslinking (22).…”

Section: Discussionmentioning

confidence: 99%

Ezrin Tunes the Magnitude of Humoral Immunity

Pore

Parameswaran

Matsui³

et al. 2013

The Journal of Immunology

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Ezrin is a member of the Ezrin-Radixin-Moesin (ERM) family of membrane-actin cytoskeleton crosslinkers that participate in a variety of cellular processes. In B cells, phosphorylation of ezrin at different sites regulates multiple processes such as lipid raft coalescence, BCR diffusion, microclustering, and endosomal JNK activation. In this study, we generated mice with conditional deletion of ezrin in the B cell lineage to investigate the physiological significance of ezrin’s function in antigen receptor-mediated B cell activation and humoral immunity. B cell development, as well as the proportion and numbers of major B cell subsets in peripheral lymphoid organs were unaffected by the loss of ezrin. Using super resolution imaging methods we show that in the absence of ezrin, BCRs respond to antigen binding by accumulating into larger and more stable signaling microclusters. Loss of ezrin led to delayed BCR capping and accelerated lipid raft coalescence. While proximal signaling proteins showed stronger activation in the absence of ezrin, components of the distal BCR signaling components displayed distinct effects. Ezrin deficiency resulted in increased B cell proliferation and differentiation into antibody-secreting cells ex vivo, and stronger T cell-independent and -dependent responses to antigen in vivo. Overall, our data demonstrate that ezrin regulates amplification of BCR signals and tunes the strength of B cell activation and humoral immunity.

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“…Myosin II activity is essential for the localization of ERM proteins to the uropod, where ERM proteins in turn regulate Rho activity providing a positive feedback loop that sustains uropod formation. ERM proteins are necessary for efficient migration, and interact with flotillins to form lipid raft clusters at the uropod (Chen et al, 2013, Serrador et al, 1997, Tomas et al, 2002). Accordingly, uropod formation and myosin II activity are impaired in neutrophils from flotillin 1 knockout mice (Ludwig et al, 2010).…”

Section: Signaling and The Neutrophil Uropodmentioning

confidence: 99%

Leading from the Back: The Role of the Uropod in Neutrophil Polarization and Migration

2016

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Cell motility is required for diverse biological processes including development, homing of immune cells, wound healing, and cancer cell invasion. Motile neutrophils exhibit a polarized morphology characterized by the formation of leading edge pseudopods and a highly contractile cell rear known as the uropod. Although it is known that perturbing uropod formation impairs neutrophil migration, the role of the uropod in cell polarization and motility remains incompletely understood. Here we discuss cell intrinsic mechanisms that regulate neutrophil polarization and motility with a focus on the uropod, and examine how relationships among regulatory mechanisms change when cells change their direction of migration.

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Ezrin and Moesin Are Required for Efficient T Cell Adhesion and Homing to Lymphoid Organs

Cited by 27 publications

References 75 publications

Ezrin/Radixin/Moesin Proteins and Flotillins Cooperate to Promote Uropod Formation in T Cells

Ezrin/Radixin/Moesin Proteins and Flotillins Cooperate to Promote Uropod Formation in T Cells

Ezrin Tunes the Magnitude of Humoral Immunity

Leading from the Back: The Role of the Uropod in Neutrophil Polarization and Migration

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