title: Alternative splicing of MALT1 controls signalling and activation of CD4(+) T cells.
abstract: MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. With MALT1A and MALT1B two conserved splice variants exist and we demonstrate here that MALT1 alternative splicing supports optimal T-cell activation. Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. Naive CD4(+) T cells express almost exclusively MALT1B and MALT1A expression is induced by TCR stimulation. We identify hnRNP U as a suppressor of exon7 inclusion. Whereas selective depletion of MALT1A impairs T-cell signalling and activation, downregulation of hnRNP U enhances MALT1A expression and T-cell activation. Thus, TCR-induced alternative splicing augments MALT1 scaffolding to enhance downstream signalling and to promote optimal T-cell activation.
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Meininger
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.|Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstrasse 55, 72770 Reutlingen, Germany.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Griesbach
authors.affiliation: Research Unit Molecular Immune Regulation, Helmholtz Zentrum München-German Research Center for Environmental Health, Marchioninistrsse 25, 81377 München, Germany.|Institute for Immunology, Biomedical Center Munich, LMU Munich, Grosshaderner Strsse 9, 82152 Martinsried, Germany.
authors.forename: Desheng
authors.initials: D
authors.lastname: Hu
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Gehring
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seeholzer
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bertossi
authors.affiliation: Institute for Immunology, Biomedical Center Munich, LMU Munich, Grosshaderner Strsse 9, 82152 Martinsried, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kranich
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Oeckinghaus
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Eitelhuber
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Greczmiel
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gewies
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Molecular Immunopathology &Signal Transduction, III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|German Center for Infection Research (DZIF), partner site Munich, 81675 München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Institute for Immunology, Biomedical Center Munich, LMU Munich, Grosshaderner Strsse 9, 82152 Martinsried, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brocker
authors.affiliation: Research Unit Molecular Immune Regulation, Helmholtz Zentrum München-German Research Center for Environmental Health, Marchioninistrsse 25, 81377 München, Germany.|Institute for Immunology, Biomedical Center Munich, LMU Munich, Grosshaderner Strsse 9, 82152 Martinsried, Germany.
authors.forename: Vigo
authors.initials: V
authors.lastname: Heissmeyer
authors.affiliation: Free University Berlin, Institute of Chemistry and Biochemistry, RNA Biochemistry, Takustrasse 6, 14195 Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Heyd
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D005091:Exons / Q000235:genetics; D057809:HEK293 Cells; D034722:Heterogeneous-Nuclear Ribonucleoprotein U / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008810:Mice, Inbred C57BL; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D015854:Up-Regulation
chemical_list: D034722:Heterogeneous-Nuclear Ribonucleoprotein U; D007376:Interleukin-2; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D048029:TNF Receptor-Associated Factor 6; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; C400109:MALT1 protein, human; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein