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Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation.
- Source :
-
Cell reports [Cell Rep] 2014 Nov 20; Vol. 9 (4), pp. 1292-305. Date of Electronic Publication: 2014 Nov 13. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
B-Lymphocytes immunology
Caspases deficiency
Cell Differentiation immunology
Gene Expression Regulation
Homeostasis immunology
Humans
Immunity, Mucosal immunology
Interferon-gamma biosynthesis
Lymphocyte Activation immunology
Mice, Mutant Strains
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
Neoplasm Proteins deficiency
Nerve Degeneration immunology
Nerve Degeneration pathology
RNA, Messenger genetics
RNA, Messenger metabolism
Receptors, Antigen, T-Cell metabolism
Signal Transduction immunology
T-Lymphocytes, Regulatory immunology
Autoimmunity
Caspases metabolism
Inflammation immunology
Inflammation pathology
Neoplasm Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 25456129
- Full Text :
- https://doi.org/10.1016/j.celrep.2014.10.044