title: Discs Large Homolog 1 Splice Variants Regulate p38-Dependent and -Independent Effector Functions in CD8+ T Cells.
abstract: Functionally diverse CD8+ T cells develop in response to antigenic stimulation with differing capacities to couple TCR engagement to downstream signals and functions. However, mechanisms of diversifying TCR signaling are largely uncharacterized. Here we identified two alternative splice variants of scaffold protein Dlg1, Dlg1AB and Dlg1B, that diversify signaling to regulate p38-dependent and -independent effector functions in CD8+ T cells. Dlg1AB, but not Dlg1B associated with Lck, coupling TCR stimulation to p38 activation and proinflammatory cytokine production. Conversely, both Dlg1AB and Dlg1B mediated p38-independent degranulation. Degranulation depended on a Dlg1 fragment containing an intact Dlg1SH3-domain and required the SH3-ligand WASp. Further, Dlg1 controlled WASp activation by promoting TCR-triggered conformational opening of WASp. Collectively, our data support a model where Dlg1 regulates p38-dependent proinflammatory cytokine production and p38-independent cytotoxic granule release through the utilization of alternative splice variants, providing a mechanism whereby TCR engagement couples downstream signals to unique effector functions in CD8+ T cells.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Oscar
authors.initials: O
authors.lastname: Silva
authors.affiliation: Molecular Biology Interdepartmental Program, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jillian
authors.initials: J
authors.lastname: Crocetti
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Humphries
authors.affiliation: Department of Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Janis K
authors.initials: JK
authors.lastname: Burkhardt
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: M Carrie
authors.initials: MC
authors.lastname: Miceli
mesh_terms: D000199:Actins / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D015550:Cell Degranulation; D016207:Cytokines / Q000235:genetics; D000074288:Discs Large Homolog 1 Protein; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D053804:Granzymes / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D058105:Polymerization; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D000074407:SAP90-PSD95 Associated Proteins; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D016207:Cytokines; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D018836:Inflammation Mediators; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; D011948:Receptors, Antigen, T-Cell; D000074407:SAP90-PSD95 Associated Proteins; D014409:Tumor Necrosis Factor-alpha; D051316:Wiskott-Aldrich Syndrome Protein; D007371:Interferon-gamma; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D048051:p38 Mitogen-Activated Protein Kinases; D053804:Granzymes