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Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation

Please always quote using this URN: urn:nbn:de:bvb:20-opus-114627
  • 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-kappa B activation, and its proteolytic domain cleaves negative NF-kappa B 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 regulatoryThe 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-kappa B activation, and its proteolytic domain cleaves negative NF-kappa B 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-kappa B 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 (IFN gamma) 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.show moreshow less

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Metadaten
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, Juergen Ruland
URN:urn:nbn:de:bvb:20-opus-114627
Document Type:Journal article
Faculties:Medizinische Fakultät / Pathologisches Institut
Language:English
Parent Title (English):Cell Reports
Year of Completion:2014
Volume:9
Issue:4
Pagenumber:1292-1305
Source:Cell Reports 9, 1292–1305, November 20, 2014. DOI: 10.1016/j.celrep.2014.10.044
DOI:https://doi.org/10.1016/j.celrep.2014.10.044
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25456129
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:NF-KAPPA-B; activation; cleavage; combined immunodeficiency; helper T-cells; lymphoid-tissue; messenger RNA; mice; mutations; roquin
Release Date:2015/07/10
EU-Project number / Contract (GA) number:261492
EU-Project number / Contract (GA) number:322865
OpenAIRE:OpenAIRE
Licence (German):License LogoCC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitung