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  - Mayer, Alexander E.
A1  - Löffler, Mona C.
A1  - Loza Valdés, Angel E.
A1  - Schmitz, Werner
A1  - El-Merahbi, Rabih
A1  - Trujillo-Viera, Jonathan
A1  - Erk, Manuela
A1  - Zhang, Thianzhou
A1  - Braun, Ursula
A1  - Heikenwalder, Mathias
A1  - Leitges, Michael
A1  - Schulze, Almut
A1  - Sumara, Grzegorz
T1  - The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling
JF  - Science Signaling
N2  - Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.
KW  - Protein kinase D3 (PKD3)
KW  - cholesterol
KW  - diacylglycerol (DAG)
KW  - liver
KW  - metabolism
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250025
ET  - accepted manuscript
ER  -