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Dive into the research topics where Christian Preisinger is active.

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Featured researches published by Christian Preisinger.


FEBS Journal | 2013

Mechanism of dual specificity kinase activity of DYRK1A

Agnes Walte; Katharina Rüben; Ruth Birner-Gruenberger; Christian Preisinger; Simone Bamberg-Lemper; Nikolaus Hilz; Franz Bracher; Walter Becker

The function of many protein kinases is controlled by the phosphorylation of a critical tyrosine residue in the activation loop. Dual specificity tyrosine‐phosphorylation‐regulated kinases (DYRKs) autophosphorylate on this tyrosine residue but phosphorylate substrates on aliphatic amino acids. This study addresses the mechanism of dual specificity kinase activity in DYRK1A and related kinases. Tyrosine autophosphorylation of DYRK1A occurred rapidly during in vitro translation and did not depend on the non‐catalytic domains or other proteins. Expression in bacteria as well as in mammalian cells revealed that tyrosine kinase activity of DYRK1A is not restricted to the co‐translational autophosphorylation in the activation loop. Moreover, mature DYRK1A was still capable of tyrosine autophosphorylation. Point mutants of DYRK1A and DYRK2 lacking the activation loop tyrosine showed enhanced tyrosine kinase activity. A series of structurally diverse DYRK1A inhibitors was used to pharmacologically distinguish different conformational states of the catalytic domain that are hypothesized to account for the dual specificity kinase activity. All tested compounds inhibited substrate phosphorylation with higher potency than autophosphorylation but none of the tested inhibitors differentially inhibited threonine and tyrosine kinase activity. Finally, the related cyclin‐dependent kinase‐like kinases (CLKs), which lack the activation loop tyrosine, autophosphorylated on tyrosine both in vitro and in living cells. We propose a model of DYRK autoactivation in which tyrosine autophosphorylation in the activation loop stabilizes a conformation of the catalytic domain with enhanced serine/threonine kinase activity without disabling tyrosine phosphorylation. The mechanism of dual specificity kinase activity probably applies to related serine/threonine kinases that depend on tyrosine autophosphorylation for maturation.


Hepatology | 2016

IκB kinaseα/β control biliary homeostasis and hepatocarcinogenesis in mice by phosphorylating the cell‐death mediator receptor‐interacting protein kinase 1

Christiane Koppe; Patricia Verheugd; Jérémie Gautheron; Florian Reisinger; Karina Kreggenwinkel; Christoph Roderburg; Luca Quagliata; Luigi Terracciano; Nikolaus Gassler; Rene Tolba; Yannick Boege; Achim Weber; Michael Karin; Mark Luedde; Ulf P. Neumann; Ralf Weiskirchen; Frank Tacke; Mihael Vucur; Christian Trautwein; Bernhard Lüscher; Christian Preisinger; Mathias Heikenwalder; Tom Luedde

The IκB‐Kinase (IKK) complex—consisting of the catalytic subunits, IKKα and IKKβ, as well as the regulatory subunit, NEMO—mediates activation of the nuclear factor κB (NF‐κB) pathway, but previous studies suggested the existence of NF‐κB‐independent functions of IKK subunits with potential impact on liver physiology and disease. Programmed cell death is a crucial factor in the progression of liver diseases, and receptor‐interacting kinases (RIPKs) exerts strategic control over multiple pathways involved in regulating novel programmed cell‐death pathways and inflammation. We hypothesized that RIPKs might be unrecognized targets of the catalytic IKK‐complex subunits, thereby regulating hepatocarcinogenesis and cholestasis. In this present study, mice with specific genetic inhibition of catalytic IKK activity in liver parenchymal cells (LPCs; IKKα/βLPC‐KO) were intercrossed with RIPK1LPC‐KO or RIPK3−/− mice to examine whether RIPK1 or RIPK3 might be downstream targets of IKKs. Moreover, we performed in vivo phospho‐proteome analyses and in vitro kinase assays, mass spectrometry, and mutagenesis experiments. These analyses revealed that IKKα and IKKβ—in addition to their known function in NF‐κB activation—directly phosphorylate RIPK1 at distinct regions of the protein, thereby regulating cell viability. Loss of this IKKα/β‐dependent RIPK1 phosphorylation in LPCs inhibits compensatory proliferation of hepatocytes and intrahepatic biliary cells, thus impeding HCC development, but promoting biliary cell paucity and lethal cholestasis. Conclusions: IKK‐complex subunits transmit a previously unrecognized signal through RIPK1, which is fundamental for the long‐term consequences of chronic hepatic inflammation and might have potential implications for future pharmacological strategies against cholestatic liver disease and cancer. (Hepatology 2016;64:1217‐1231)


Cancer Cell | 2017

RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

Anne T. Schneider; Jérémie Gautheron; Maria Feoktistova; Christoph Roderburg; Sven H. Loosen; Sanchari Roy; Fabian Benz; Peter Schemmer; Markus W. Büchler; Ueli Nachbur; Ulf P. Neumann; Rene Tolba; Mark Luedde; Jessica Zucman-Rossi; Diana Panayotova-Dimitrova; Martin Leverkus; Christian Preisinger; Frank Tacke; Christian Trautwein; Thomas Longerich; Mihael Vucur; Tom Luedde

Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis.


Journal of Hepatology | 2016

Keratin 23 is a stress-inducible marker of mouse and human ductular reaction in liver disease

Nurdan Guldiken; Gokce Kobazi Ensari; Pooja Lahiri; Gabrielle Couchy; Christian Preisinger; Christian Liedtke; Henning W. Zimmermann; Marianne Ziol; Peter Boor; Jessica Zucman-Rossi; Christian Trautwein; Pavel Strnad

BACKGROUND & AIMS Keratins (K) constitute the epithelial intermediate filaments. Among them, K7/K19 are widely used markers of the regenerative liver response termed ductular reaction (DR) that consists of activated biliary epithelial cells (BECs) and hepatic progenitor cells (HPCs) and correlates with liver disease severity. In the present study we aimed to characterize K23 in the liver. METHODS We analyzed the expression and localization of K23 in the digestive system under basal conditions as well as in various human and mouse liver diseases/stress models. Cell culture studies were used to study factors regulating K23 expression. RESULTS In untreated mice, K23 was restricted to biliary epithelia. It was (together with K7/K19) markedly upregulated in three different DR/cholestatic injury models, i.e., multidrug resistance protein 2 (Mdr2) knockouts, animals treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine or subjected to bile duct ligation. K23 levels correlated with the DR marker Fn14 and immunofluorescence staining showed a distinct co-localization with K7/K19. In chronic human liver disease, K23 expression increased in patients with a more prominent inflammation/fibrosis. A dramatic upregulation (>200times) was observed in patients with acute liver failure (ALF) and end-stage primary biliary cholangitis (PBC). Patients with alcoholic liver cirrhosis displayed increased K23 serum levels. In primary hepatocytes as well as hepatobiliary cell lines, treatment with TNF-related weak inducer of apoptosis (TWEAK), and the type I acute phase inducer interleukin (IL)-1β but not the type II inducer IL-6 elevated K23 expression. CONCLUSIONS K23 represents a specific, stress-inducible DR marker, whose levels correlate with liver disease severity. K23 may represent a useful non-invasive DR marker. LAY SUMMARY Ductular reaction represents a basic response to liver injury and correlates with liver disease severity. Our study identifies K23 as a novel ductular reaction marker in mice and humans.


The EMBO Journal | 2016

Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice.

Siv Vingill; David Brockelt; Camille Lancelin; Lars Tatenhorst; Guergana Dontcheva; Christian Preisinger; Nicola Schwedhelm-Domeyer; Sabitha Joseph; Miso Mitkovski; Sandra Goebbels; Klaus-Armin Nave; Jörg B. Schulz; Till Marquardt; Paul Lingor; Judith Stegmüller

Mutations in the FBXO7 (PARK15) gene have been implicated in a juvenile form of parkinsonism termed parkinsonian pyramidal syndrome (PPS), characterized by Parkinsonian symptoms and pyramidal tract signs. FBXO7 (F‐box protein only 7) is a subunit of the SCF (SKP1/cullin‐1/F‐box protein) E3 ubiquitin ligase complex, but its relevance and function in neurons remain to be elucidated. Here, we report that the E3 ligase FBXO7‐SCF binds to and ubiquitinates the proteasomal subunit PSMA2. In addition, we show that FBXO7 is a proteasome‐associated protein involved in proteasome assembly. In FBXO7 knockout mice, we find reduced proteasome activity and early‐onset motor deficits together with premature death. In addition, we demonstrate that NEX (neuronal helix–loop–helix protein‐1)‐Cre‐induced deletion of the FBXO7 gene in forebrain neurons or the loss of FBXO7 in tyrosine hydroxylase (TH)‐positive neurons results in motor defects, reminiscent of the phenotype in PARK15 patients. Taken together, our study establishes a vital role for FBXO7 in neurons, which is required for proper motor control and accentuates the importance of FBXO7 in proteasome function.


Journal of Biological Chemistry | 2016

AMP-activated Protein Kinase Up-regulates Mitogen-activated Protein (MAP) Kinase-interacting Serine/Threonine Kinase 1a-dependent Phosphorylation of Eukaryotic Translation Initiation Factor 4E

Xiaoqing Zhu; V.E.H. Dahlmans; Ramon F. Thali; Christian Preisinger; Benoit Viollet; J. Willem Voncken; Dietbert Neumann

AMP-activated protein kinase (AMPK) is a molecular energy sensor that acts to sustain cellular energy balance. Although AMPK is implicated in the regulation of a multitude of ATP-dependent cellular processes, exactly how these processes are controlled by AMPK as well as the identity of AMPK targets and pathways continues to evolve. Here we identify MAP kinase-interacting serine/threonine protein kinase 1a (MNK1a) as a novel AMPK target. Specifically, we show AMPK-dependent Ser353 phosphorylation of the human MNK1a isoform in cell-free and cellular systems. We show that AMPK and MNK1a physically interact and that in vivo MNK1a-Ser353 phosphorylation requires T-loop phosphorylation, in good agreement with a recently proposed structural regulatory model of MNK1a. Our data suggest a physiological role for MNK1a-Ser353 phosphorylation in regulation of the MNK1a kinase, which correlates with increased eIF4E phosphorylation in vitro and in vivo.


Mucosal Immunology | 2018

Desmoglein 2, but not desmocollin 2, protects intestinal epithelia from injury

Annika Gross; Lotta Antonia Pauline Pack; Gabriel M. Schacht; Sebastian Kant; Hanna Ungewiss; Michael Meir; Nicolas Schlegel; Christian Preisinger; Peter Boor; Nurdan Guldiken; Claudia A. Krusche; Gernot Sellge; Christian Trautwein; Jens Waschke; Arnd Heuser; Rudolf E. Leube; Pavel Strnad

Desmosomes are the least understood intercellular junctions in the intestinal epithelia and provide cell–cell adhesion via the cadherins desmoglein (Dsg)2 and desmocollin (Dsc)2. We studied these cadherins in Crohn’s disease (CD) patients and in newly generated conditional villin-Cre DSG2 and DSC2 knockout mice (DSG2ΔIEC; DSC2ΔIEC). CD patients exhibited altered desmosomes and reduced Dsg2/Dsc2 levels. The intestines of both transgenic animal lines were histopathologically inconspicuous. However, DSG2ΔIEC, but not DSC2ΔIEC mice displayed an increased intestinal permeability, a wider desmosomal space as well as alterations in desmosomal and tight junction components. After dextran sodium sulfate (DSS) treatment and Citrobacter rodentium exposure, DSG2ΔIEC mice developed a more-pronounced colitis, an enhanced intestinal epithelial barrier disruption, leading to a stronger inflammation and activation of epithelial pSTAT3 signaling. No susceptibility to DSS-induced intestinal injury was noted in DSC2ΔIEC animals. Dsg2 interacted with the cytoprotective chaperone Hsp70. Accordingly, DSG2ΔIEC mice had lower Hsp70 levels in the plasma membrane compartment, whereas DSC2ΔIEC mice displayed a compensatory recruitment of galectin 3, a junction-tightening protein. Our results demonstrate that Dsg2, but not Dsc2 is required for the integrity of the intestinal epithelial barrier in vivo.


Gastroenterology | 2016

Combined activities of JNK1 and JNK2 in hepatocytes protect against toxic liver injury

F.J. Cubero; Miguel Eugenio Zoubek; Wei Hu; Jin Peng; Gang Zhao; Yulia A. Nevzorova; Malika Al Masaoudi; Lars P. Bechmann; Mark V. Boekschoten; Michael Müller; Christian Preisinger; Nikolaus Gassler; Ali Canbay; Tom Luedde; Roger J. Davis; Christian Liedtke; Christian Trautwein


Scientific Reports | 2018

Nucleolar-nucleoplasmic shuttling of TARG1 and its control by DNA damage-induced poly-ADP-ribosylation and by nucleolar transcription

Mareike Bütepage; Christian Preisinger; Alexander von Kriegsheim; Anja Scheufen; Eva Lausberg; Jinyu Li; Ferdinand Kappes; Regina Feederle; Sabrina Ernst; Laura Eckei; Sarah Krieg; Gerhard Müller-Newen; Giulia Rossetti; Karla L. H. Feijs; Patricia Verheugd; Bernhard Lüscher


Journal of Hepatology | 2016

IKKALPHA/Beta Regulate Hepatocarcinogenesis and Biliary Homeostasis by Controlling RIPK1 Activity

C. Koppe; F. Reisinger; P. Verheugd; Jérémie Gautheron; Christoph Roderburg; Frank Tacke; Christian Preisinger; B. Lüscher; Mihael Vucur; C Trautwein; Mathias Heikenwalder; T Luedde

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Tom Luedde

RWTH Aachen University

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Frank Tacke

RWTH Aachen University

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