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

• Published in: Cell reports (Cambridge) Vol. 9; no. 4; pp. 1292 - 1305
• Main Authors: Gewies, Andreas, Gorka, Oliver, Bergmann, Hanna, Pechloff, Konstanze, Petermann, Franziska, Jeltsch, Katharina M., Rudelius, Martina, Kriegsmann, Mark, Weichert, Wilko, Horsch, Marion, Beckers, Johannes, Wurst, Wolfgang, Heikenwalder, Mathias, Korn, Thomas, Heissmeyer, Vigo, Ruland, Jürgen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.11.2014; Elsevier
• Subjects: Animals; Autoimmunity; B-Lymphocytes - immunology; Caspases - deficiency; Caspases - metabolism; Cell Differentiation - immunology; Gene Expression Regulation; Homeostasis - immunology; Humans; Immunity, Mucosal - immunology; Inflammation - immunology; Inflammation - pathology; Interferon-gamma - biosynthesis; Lymphocyte Activation - immunology; Mice, Mutant Strains; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Neoplasm Proteins - deficiency; Neoplasm Proteins - metabolism; Nerve Degeneration - immunology; Nerve Degeneration - pathology; Receptors, Antigen, T-Cell - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.10.044

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. [Display omitted] •The Malt1 scaffold and Malt1 paracaspase activity have differential functions in vivo•Malt1 protease activity is essential for Treg and innate-like B cell development•Paracaspase activity controls NF-κB and mRNA stability regulators•Malt1 paracaspase activity prevents destructive autoinflammation The paracaspase Malt1 is a key regulator of antigen receptor signaling and frequently mutated in human lymphoma. Gewies et al. demonstrate that the proteolytic function of Malt1 is largely dispensable for lymphocyte activation but critical for regulatory T cell (Treg) and innate-like B cell development and protection from IFNγ-mediated autoinflammation in vivo.