TY  - JOUR
A1  - Gewies, Andreas
A1  - Gorka, Oliver
A1  - Bergmann, Hanna
A1  - Pechloff, Konstanze
A1  - Petermann, Franziska
A1  - Jeltsch, Katharina M.
A1  - Rudelius, Martina
A1  - Kriegsmann, Mark
A1  - Weichert, Wilko
A1  - Horsch, Marion
A1  - Beckers, Johannes
A1  - Wurst, Wolfgang
A1  - Heikenwalder, Mathias
A1  - Korn, Thomas
A1  - Heissmeyer, Vigo
A1  - Ruland, Juergen
T1  - Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation
JF  - Cell Reports
N2  - 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 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.
KW  - helper T-cells
KW  - combined immunodeficiency
KW  - messenger RNA
KW  - roquin
KW  - mice
KW  - NF-KAPPA-B
KW  - lymphoid-tissue
KW  - activation
KW  - cleavage
KW  - mutations
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114627
VL  - 9
IS  - 4
ER  - 
TY  - JOUR
A1  - Wille, Michael
A1  - Schümann, Antje
A1  - Wree, Andreas
A1  - Kreutzer, Michael
A1  - Glocker, Michael O.
A1  - Mutzbauer, Grit
A1  - Schmitt, Oliver
T1  - The Proteome Profiles of the Cerebellum of Juvenile, Adult and Aged Rats-An Ontogenetic Study
JF  - International Journal of Molecular Sciences
N2  - In this study, we searched for proteins that change their expression in the cerebellum (Ce) of rats during ontogenesis. This study focuses on the question of whether specific proteins exist which are differentially expressed with regard to postnatal stages of development. A better characterization of the microenvironment and its development may result from these study findings. A differential two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis of the samples revealed that the number of proteins of the functional classes differed depending on the developmental stages. Especially members of the functional classes of biosynthesis, regulatory proteins, chaperones and structural proteins show the highest differential expression within the analyzed stages of development. Therefore, members of these functional protein groups seem to be involved in the development and differentiation of the Ce within the analyzed development stages. In this study, changes in the expression of proteins in the Ce at different postnatal developmental stages (postnatal days (P) 7, 90, and 637) could be observed. At the same time, an identification of proteins which are involved in cell migration and differentiation was possible. Especially proteins involved in processes of the biosynthesis and regulation, the dynamic organization of the cytoskeleton as well as chaperones showed a high amount of differentially expressed proteins between the analyzed dates.
KW  - messenger RNA
KW  - brain
KW  - cerebellum
KW  - development
KW  - proteomics
KW  - rat
KW  - proteins
KW  - adenosine kinase
KW  - coated vesicles
KW  - phosphatase 2A
KW  - expression
KW  - neuronal differentiation
KW  - human brain
KW  - hnRNP K
KW  - postnatal development
KW  - binding
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151347
VL  - 16
SP  - 21454
EP  - 21485
ER  -