title: IκB kinaseα/β control biliary homeostasis and hepatocarcinogenesis in mice by phosphorylating the cell-death mediator receptor-interacting protein kinase 1.
abstract: 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.
  
  
  
  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).
authors.affiliation: Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Koppe
authors.affiliation: Institute of Biochemistry and Molecular Biology, University Hospital RWTH Aachen University, Aachen, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Verheugd
authors.affiliation: Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Gautheron
authors.affiliation: Department of Virology, Technische Universität München/Helmholtz Zentrum München für Gesundheit und Umwelt (HMGU), Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Reisinger
authors.affiliation: Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Karina
authors.initials: K
authors.lastname: Kreggenwinkel
authors.affiliation: Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Roderburg
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Institute of Pathology, Hospital of Braunschweig, Braunschweig, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.affiliation: Department of Laboratory Animal Research, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: René H
authors.initials: RH
authors.lastname: Tolba
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Boege
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Department of Pharmacology and Pathology, School of Medicine, UCSD, La Jolla, CA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Luedde
authors.affiliation: Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Ulf P
authors.initials: UP
authors.lastname: Neumann
authors.affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.affiliation: Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.affiliation: Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Institute of Biochemistry and Molecular Biology, University Hospital RWTH Aachen University, Aachen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.affiliation: Proteomics Facility, Interdisciplinary Center for Clinical Research (IZKF) Aachen, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Preisinger
authors.affiliation: Department of Virology, Technische Universität München/Helmholtz Zentrum München für Gesundheit und Umwelt (HMGU), Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany. tluedde@ukaachen.de.
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic; D063646:Carcinogenesis; D006706:Homeostasis; D051550:I-kappa B Kinase / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C470629:MIB1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase