Christian Preisinger

RWTH Aachen University

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Christian Trautwein

RWTH Aachen University

Francis A. Barr

University of Oxford

Walter Kölch

University College Dublin

Albert J. R. Heck

Utrecht University

Pavel Strnad

RWTH Aachen University

Tom Luedde

Heinrich Heine University Düsseldorf

Ulf P. Neumann

RWTH Aachen University

Frank Tacke

Charité - Universitätsmedizin Berlin

Robert Kopajtich

Technical University of Munich

Nurdan Güldiken

RWTH Aachen University

Cooperative Institutions

Canon (Japan)

213

European Foundation for the Study of Chronic Liver Failure

212

RWTH Aachen University

190

Universitätsklinikum Aachen

132

Inserm

Heidelberg University

Utrecht University

Assistance Publique – Hôpitaux de Paris

Max Planck Society

Université Paris Cité

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

Mucosal Immunology (2018)

Annika Groß Lotta Antonia Pauline Pack Gabriel M. Schacht Sebastian Kant Hanna Ungewiß

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.

Desmoglein 1

10.1038/s41385-018-0062-z

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

Journal of Hepatology (2016)

Nurdan Güldiken Gökce Kobazi Ensari Pooja Lahiri Gabrielle Couchy Christian Preisinger

Hepatic stellate cell

10.1016/j.jhep.2016.04.024

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Citations (38)

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

Hepatology (2016)

Christiane Koppe Patricia Verheugd Jérémie Gautheron Florian Reisinger Karina Kreggenwinkel

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/β LPC‐KO ) were intercrossed with RIPK1 LPC‐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. (H epatology 2016;64:1217‐1231)

IκB kinase

10.1002/hep.28723

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Citations (52)

Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia

Carcinogenesis (2020)

Margherita Vieri Christian Preisinger Mirle Schemionek Azam Salimi John B. Patterson

BCR-ABL1-positive acute lymphoblastic leukemia (ALL) cell survival is dependent on the inositol-requiring enzyme 1 alpha (IRE1α) branch of the unfolded protein response. In the current study, we have focused on exploring the efficacy of a simultaneous pharmacological inhibition of BCR-ABL1 and IRE1α in Philadelphia-positive (Ph+) ALL using tyrosine kinase inhibitor (TKI) nilotinib and the IRE1α inhibitor MKC-8866. The combination of 0.5 µM nilotinib and 30 µM MKC-8866 in Ph+ ALL cell lines led to a synergistic effect on cell viability. To mimic this dual inhibition on a genetic level, pre-B-cells from conditional Xbp1+/fl mice were transduced with a BCR-ABL1 construct and with either tamoxifen-inducible cre or empty vector. Cells showed a significant sensitization to the effect of TKIs after the induction of the heterozygous deletion. Finally, we performed a phosphoproteomic analysis on Ph+ ALL cell lines treated with the combination of nilotinib and MKC-8866 to identify potential targets involved in their synergistic effect. An enhanced activation of p38 mitogen-activated protein kinase α (p38α MAPK) was identified. In line with this findings, p38 MAPK and, another important endoplasmic reticulum-stress-related kinase, c-Jun N-terminal kinase (JNK) were found to mediate the potentiated cytotoxic effect induced by the combination of MKC-8866 and nilotinib since the targeting of p38 MAPK with its specific inhibitor BIRB-796 or JNK with JNK-in-8 hindered the synergistic effect observed upon treatment with nilotinib and MKC-8866. In conclusion, the identified combined action of nilotinib and MKC-8866 might represent a successful therapeutic strategy in high-risk Ph+ ALL.

10.1093/carcin/bgaa095

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A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity

Research Square (Research Square) (2023)

Selcan Kahveci-Türköz Katharina Bläsius Justyna Woźniak Cindy Rinkens Anke Seifert

Abstract Several membrane-anchored signal mediators such as cytokines (e.g., TNFα) and growth factors are proteolytically shed from the cell surface by the metalloproteinase ADAM17, which thus has an essential role in inflammatory and developmental processes. The membrane proteins iRhom1 and iRhom2 are instrumental for the transport of ADAM17 to the cell surface and its regulation. However, the structure-function determinants of the iRhom-ADAM17 complex are poorly understood. We used AI-based modelling to gain insights into the structure-function relationship of this complex. We identified different regions in the iRhom homology domain (IRHD) that are differentially responsible for iRhom functions. We have supported the validity of the predicted structure-function determinants with several in vitro, ex vivo and in vivo approaches and demonstrated the regulatory role of the IRHD for iRhom-ADAM17 complex cohesion and forward trafficking. Overall, we provide mechanistic insights into the iRhom-ADAM17-mediated shedding event, which is at the centre of several important cytokine and growth factor pathways.

Cell surface receptor

10.21203/rs.3.rs-2526407/v1

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Citations (1)

Die Kinase RIPK1 vermittelt eine neue molekulare Interaktion zwischen Entzündung und Zelltod in der Hepatokarzinogenese und Cholestase

Zeitschrift für Gastroenterologie (2015)

Christiane Koppe Florian Reisinger P Verheugd Jérémie Gautheron Christoph Roderburg

Zelltod und Entzündung sind entscheidend für die Hepatokarzinogenese. Der NF-κB-Signalweg, der durch den IKK-Komplex – bestehend aus den katalytischen Einheiten IKK1 und IKK2 sowie der regulatorischen Einheit NEMO – aktiviert wird, spielt dabei eine wichtige Rolle. So führt die Deletion von NEMO in Leberzellen (NEMO-KO) über die Aktivierung von Apoptose, kompensatorischer Regeneration und Inflammation zur spontanen Leberkrebsentstehung. Neben der Apoptose existieren weitere Zelltodsignalwege wie die Nekroptose, welche über die Kinasen RIPK1 und RIPK3 reguliert wird. Zurzeit ist nicht vollständig geklärt, wie diese Signalwege mit dem NF-κB-Signalweg interagieren und welche Rolle sie in der Karzinogenese spielen.

10.1055/s-0035-1568060

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The iRhom homology domain is indispensable for ADAM17-mediated TNFα and EGF receptor ligand release

Cellular and Molecular Life Sciences (2021)

Stefan Düsterhöft Selcan Kahveci-Türköz Justyna Wozniak Anke Seifert Petr Kašpárek

Membrane-tethered signalling proteins such as TNFα and many EGF receptor ligands undergo shedding by the metalloproteinase ADAM17 to get released. The pseudoproteases iRhom1 and iRhom2 are important for the transport, maturation and activity of ADAM17. Yet, the structural and functional requirements to promote the transport of the iRhom-ADAM17 complex have not yet been thoroughly investigated. Utilising in silico and in vitro methods, we here map the conserved iRhom homology domain (IRHD) and provide first insights into its structure and function. By focusing on iRhom2, we identified different structural and functional factors within the IRHD. We found that the structural integrity of the IRHD is a key factor for ADAM17 binding. In addition, we identified a highly conserved motif within an unstructured region of the IRHD, that, when mutated, restricts the transport of the iRhom-ADAM17 complex through the secretory pathway in in vitro, ex vivo and in vivo systems and also increases the half-life of iRhom2 and ADAM17. Furthermore, the disruption of this IRHD motif was also reflected by changes in the yet undescribed interaction profile of iRhom2 with proteins involved in intracellular vesicle transport. Overall, we provide the first insights into the forward trafficking of iRhoms which is critical for TNFα and EGF receptor signalling.

10.1007/s00018-021-03845-3

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Citations (14)

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

Scientific Reports (2018)

Mareike Bütepage Christian Preisinger Alex von Kriegsheim Anja Scheufen Eva Lausberg

Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP-ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors. TARG1 localized to transcriptionally active nucleoli, which occurred independently of ADP-ribose binding. TARG1 shuttled continuously between nucleoli and nucleoplasm. In response to DNA damage, which activates ARTD1/2 (PARP1/2) and promotes synthesis of poly-ADP-ribose chains, TARG1 re-localized to the nucleoplasm. This was dependent on the ability of TARG1 to bind to poly-ADP-ribose. These findings are consistent with the observed ability of TARG1 to competitively interact with RNA and PAR chains. We propose a nucleolar role of TARG1 in ribosome assembly or quality control that is stalled when TARG1 is re-located to sites of DNA damage.

Transcription

ADP-ribosylation

10.1038/s41598-018-25137-w

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Citations (36)

IgG-Independent Co-aggregation of FcεRI and FcγRIIB Results in LYN- and SHIP1-Dependent Tyrosine Phosphorylation of FcγRIIB in Murine Bone Marrow-Derived Mast Cells

Frontiers in Immunology (2018)

Mathias Gast Christian Preisinger Falk Nimmerjahn Michael Huber

Activation of the high-affinity receptor for IgE (FcεRI) follows a bell-shaped dose-response curve. Upon supra-optimal stimulation, mast cell effector responses are down-regulated by inhibitory molecules like the SH2-containing inositol-5'-phosphatase SHIP1 and the SRC-family-kinase LYN. To identify further molecules involved in a negative regulatory signalosome, we screened for proteins showing the same pattern of tyrosine phosphorylation as SHIP1, which is tyrosine-phosphorylated strongest upon supra-optimal antigen stimulation. The low-affinity IgG receptor, FcγRIIB, was found to be most strongly phosphorylated under supra-optimal conditions. This phosphorylation is the consequence of passive, antigen/IgE-dependent and progressive co-localization of FcεRI and FcγRIIB, which is not dependent on IgG. Upon supra-optimal FcεRI cross-linking, FcγRIIB phosphorylation is executed by LYN and protected from dephosphorylation by SHIP1. Analysis of FcγRIIB-deficient bone marrow-derived mast cells revealed an ambiguous phenotype upon FcεRI cross-linking. Absence of FcγRIIB significantly diminished the level of SHIP1 phosphorylation and resulted in augmented Ca2+ mobilization. Though, degranulation and IL-6 production were not or only weakly enhanced, respectively. Altogether our data establish the LYN/FcγRIIB/SHIP1 signalosome in the context of FcεRI activation, particularly at supra-optimal antigen concentrations. The fact that SHIP1 tyrosine phosphorylation/activation not only depends on FcγRIIB, highlights the necessity for its tight backup control.

LYN

Dephosphorylation

Fc receptor

10.3389/fimmu.2018.01937

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Citations (14)

Synergistic Dual Inhibition of BCR-ABL1 and the Unfolded Protein Response Causes p38 MAPK-Mediated Cell Death and Sensitizes BCR-ABL1+ Acute Lymphoblastic Leukemia to Dexamethasone

Blood (2018)

Margherita Vieri Christian Preisinger Mirle Schemionek Azam Salimi John B. Patterson

breakpoint cluster region

10.1182/blood-2018-99-110967

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Citations (2)