Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation
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 f...
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doaj-12cfc686bc3843e8bcaf50027277af302020-11-24T21:24:36ZengElsevierCell Reports2211-12472014-11-01941292130510.1016/j.celrep.2014.10.044Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune InflammationAndreas Gewies0Oliver Gorka1Hanna Bergmann2Konstanze Pechloff3Franziska Petermann4Katharina M. Jeltsch5Martina Rudelius6Mark Kriegsmann7Wilko Weichert8Marion Horsch9Johannes Beckers10Wolfgang Wurst11Mathias Heikenwalder12Thomas Korn13Vigo Heissmeyer14Jürgen Ruland15Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, GermanyInstitut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, GermanyInstitut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, GermanyInstitut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, GermanyDepartment of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 München, GermanyInstitute for Immunology, Ludwig-Maximilians-Universität München, Goethestraße 31, 80336 München, GermanyInstitute of Pathology, Julius-Maximilians-Universität Würzburg and Comprehensive Cancer Center Main-Franken, 97080 Würzburg, GermanyInstitut für Pathologie, Universitätsklinikum Heidelberg, 69120 Heidelberg, GermanyInstitut für Pathologie, Universitätsklinikum Heidelberg, 69120 Heidelberg, GermanyHelmholtz Zentrum München – German Research Center for Environmental Health, Institute of Experimental Genetics, 85764 Neuherberg, GermanyHelmholtz Zentrum München – German Research Center for Environmental Health, Institute of Experimental Genetics, 85764 Neuherberg, GermanyHelmholtz Zentrum München – German Research Center for Environmental Health, Institute of Developmental Genetics, 85764 Neuherberg, GermanyInstitute of Virology, Technische Universität München/Helmholtz Zentrum München, 81675 München, GermanyDepartment of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 München, GermanyInstitute for Immunology, Ludwig-Maximilians-Universität München, Goethestraße 31, 80336 München, GermanyInstitut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, GermanyThe 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.http://www.sciencedirect.com/science/article/pii/S2211124714009139 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andreas Gewies Oliver Gorka Hanna Bergmann Konstanze Pechloff Franziska Petermann Katharina M. Jeltsch Martina Rudelius Mark Kriegsmann Wilko Weichert Marion Horsch Johannes Beckers Wolfgang Wurst Mathias Heikenwalder Thomas Korn Vigo Heissmeyer Jürgen Ruland |
spellingShingle |
Andreas Gewies Oliver Gorka Hanna Bergmann Konstanze Pechloff Franziska Petermann Katharina M. Jeltsch Martina Rudelius Mark Kriegsmann Wilko Weichert Marion Horsch Johannes Beckers Wolfgang Wurst Mathias Heikenwalder Thomas Korn Vigo Heissmeyer Jürgen Ruland Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation Cell Reports |
author_facet |
Andreas Gewies Oliver Gorka Hanna Bergmann Konstanze Pechloff Franziska Petermann Katharina M. Jeltsch Martina Rudelius Mark Kriegsmann Wilko Weichert Marion Horsch Johannes Beckers Wolfgang Wurst Mathias Heikenwalder Thomas Korn Vigo Heissmeyer Jürgen Ruland |
author_sort |
Andreas Gewies |
title |
Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation |
title_short |
Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation |
title_full |
Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation |
title_fullStr |
Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation |
title_full_unstemmed |
Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation |
title_sort |
uncoupling malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2014-11-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S2211124714009139 |
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