title: Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation.
abstract: The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation.
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: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gorka
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bergmann
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: Konstanze
authors.initials: K
authors.lastname: Pechloff
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Petermann
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-Universität München, Goethestraße 31, 80336 München, Germany; Helmholtz Zentrum München, Institute of Molecular Immunology, 81377 München, Germany.
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Jeltsch
authors.affiliation: Institute of Pathology, Julius-Maximilians-Universität Würzburg and Comprehensive Cancer Center Main-Franken, 97080 Würzburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.affiliation: Institut für Pathologie, Universitätsklinikum Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Kriegsmann
authors.affiliation: Institut für Pathologie, Universitätsklinikum Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Experimental Genetics, 85764 Neuherberg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Experimental Genetics, 85764 Neuherberg, Germany; Institute of Experimental Genetics, Technische Universität München-Weihenstephan, 85350 Freising-Weihenstephan, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Developmental Genetics, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 81675 München, Germany; Technische Universität München-Weihenstephan, Institute of Developmental Genetics, c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Standort München, 80336 München, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, 81675 München, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; Munich Cluster for Systems Neurology (SyNergy), 81675 München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-Universität München, Goethestraße 31, 80336 München, Germany; Helmholtz Zentrum München, Institute of Molecular Immunology, 81377 München, Germany.
authors.forename: Vigo
authors.initials: V
authors.lastname: Heissmeyer
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. Electronic address: jruland@lrz.tum.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D020169:Caspases / Q000172:deficiency / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008817:Mice, Mutant Strains; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism*; D009410:Nerve Degeneration / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein