The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published 7 February 2005. doi:10.1084/jem.20041428
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 3, 419-430
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ARTICLE

 Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells

June L. Round1, Tamar Tomassian1, Min Zhang1, Viresh Patel1, Stephen P. Schoenberger3, and M. Carrie Miceli1,2

1 Department of Microbiology, Immunology, and Molecular Genetics
2 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095
3 La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

CORRESPONDENCE M. Carrie Miceli: cmiceli{at}ucla.edu

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.

Abbreviations used: GST, glutathione S-transferase; IRF, IFN regulatory factor; MAGUK, membrane-associated guanylate kinase; siRNA, small interfering RNA; WASp, Wiskott-Aldrich syndrome protein.


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