Abstract
T-cell receptor (TCR) signalling is triggered and tuned at immunological synapses by the generation of signalling complexes that associate into dynamic microclusters. Microcluster movement is necessary to tune TCR signalling, but the molecular mechanism involved remains poorly known. We show here that the membrane-microfilament linker ezrin has an important function in microcluster dynamics and in TCR signalling through its ability to set the microtubule network organization at the immunological synapse. Importantly, ezrin and microtubules are important to down-regulate signalling events leading to Erk1/2 activation. In addition, ezrin is required for appropriate NF-AT activation through p38 MAP kinase. Our data strongly support the notion that ezrin regulates immune synapse architecture and T-cell activation through its interaction with the scaffold protein Dlg1. These results uncover a crucial function for ezrin, Dlg1 and microtubules in the organization of the immune synapse and TCR signal down-regulation. Moreover, they underscore the importance of ezrin and Dlg1 in the regulation of NF-AT activation through p38.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cytoskeletal Proteins / immunology*
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Discs Large Homolog 1 Protein
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Enzyme Activation
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Humans
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Immunological Synapses* / chemistry
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Immunological Synapses* / metabolism
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Immunological Synapses* / ultrastructure
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Jurkat Cells
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Lymphocyte Activation / immunology*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Microtubules / metabolism*
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Phosphoproteins / chemistry
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Antigen, T-Cell / immunology
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology
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T-Lymphocytes* / cytology
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T-Lymphocytes* / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cytoskeletal Proteins
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DLG1 protein, human
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Discs Large Homolog 1 Protein
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Membrane Proteins
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Phosphoproteins
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RNA, Small Interfering
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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SLP-76 signal Transducing adaptor proteins
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ezrin
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p38 Mitogen-Activated Protein Kinases