Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells.
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.
Round
June L
JL
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Tomassian
Tamar
T
Zhang
Min
M
Patel
Viresh
V
Schoenberger
Stephen P
SP
Miceli
M Carrie
MC
D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D051528:Guanylate Kinases; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011940:Receptor Aggregation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein; D051746:ZAP-70 Protein-Tyrosine Kinase
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C513314:DLG1 protein, human; D004268:DNA-Binding Proteins; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D007376:Interleukin-2; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C402726:Sh2d2a protein, mouse; D014157:Transcription Factors; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D051528:Guanylate Kinases