Lipid raft membrane compartmentalization and membrane-associated guanylate kinase (MAGUK) family molecular scaffolds function in establishing cell polarity and organizing signal transducers within epithelial cell junctions and neuronal synapses. Here, we elucidate a role for the MAGUK protein, Dlgh1, in polarized T cell synapse assembly and T cell function. We find that Dlgh1 translocates to the immune synapse and lipid rafts in response to T cell receptor (TCR)/CD28 engagement and that LckSH3-mediated interactions with Dlgh1 control its membrane targeting. TCR/CD28 engagement induces the formation of endogenous Lck–Dlgh1–Zap70–Wiskott-Aldrich syndrome protein (WASp) complexes in which Dlgh1 acts to facilitate interactions of Lck with Zap70 and WASp. Using small interfering RNA and overexpression approaches, we show that Dlgh1 promotes antigen-induced actin polymerization, synaptic raft and TCR clustering, nuclear factor of activated T cell activity, and cytokine production. We propose that Dlgh1 coordinates TCR/CD28-induced actin-driven T cell synapse assembly, signal transduction, and effector function. These findings highlight common molecular strategies used to regulate cell polarity, synapse assembly, and transducer organization in diverse cellular systems.
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7 February 2005
Article|
February 07 2005
Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells
June L. Round,
June L. Round
1Department of Microbiology, Immunology, and Molecular Genetics
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Tamar Tomassian,
Tamar Tomassian
1Department of Microbiology, Immunology, and Molecular Genetics
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Min Zhang,
Min Zhang
1Department of Microbiology, Immunology, and Molecular Genetics
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Viresh Patel,
Viresh Patel
1Department of Microbiology, Immunology, and Molecular Genetics
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Stephen P. Schoenberger,
Stephen P. Schoenberger
3La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
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M. Carrie Miceli
M. Carrie Miceli
1Department of Microbiology, Immunology, and Molecular Genetics
2Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095
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June L. Round
1Department of Microbiology, Immunology, and Molecular Genetics
Tamar Tomassian
1Department of Microbiology, Immunology, and Molecular Genetics
Min Zhang
1Department of Microbiology, Immunology, and Molecular Genetics
Viresh Patel
1Department of Microbiology, Immunology, and Molecular Genetics
Stephen P. Schoenberger
3La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
M. Carrie Miceli
1Department of Microbiology, Immunology, and Molecular Genetics
2Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095
CORRESPONDENCE M. Carrie Miceli: [email protected]
Abbreviations used: GST, glutathione S-transferase; IRF, IFN regulatory factor; MAGUK, membrane-associated guanylate kinase; siRNA, small interfering RNA; WASp, Wiskott-Aldrich syndrome protein.
Received:
July 15 2004
Accepted:
November 22 2004
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 201 (3): 419–430.
Article history
Received:
July 15 2004
Accepted:
November 22 2004
Citation
June L. Round, Tamar Tomassian, Min Zhang, Viresh Patel, Stephen P. Schoenberger, M. Carrie Miceli; Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells . J Exp Med 7 February 2005; 201 (3): 419–430. doi: https://doi.org/10.1084/jem.20041428
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