Ezrin tunes T-cell activation by controlling Dlg1 and microtubule positioning at the immunological synapse.
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.
Lasserre
Rémi
R
Institut Pasteur, Department of Immunology, Lymphocyte Cell Biology Unit, Paris, France.
Charrin
Stéphanie
S
Cuche
Céline
C
Danckaert
Anne
A
Thoulouze
Maria-Isabel
MI
de Chaumont
Fabrice
F
Duong
Tarn
T
Perrault
Nathalie
N
Varin-Blank
Nadine
N
Olivo-Marin
Jean-Christophe
JC
Etienne-Manneville
Sandrine
S
Arpin
Monique
M
Di Bartolo
Vincenzo
V
Alcover
Andrés
A
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000276:immunology*; D000074288:Discs Large Homolog 1 Protein; D004789:Enzyme Activation; D006801:Humans; D054992:Immunological Synapses / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099149:Ezrin
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099149:Ezrin; C513314:DLG1 protein, human; C092947:SLP-76 signal Transducing adaptor proteins