I kappa B Kinase alpha/beta Control Biliary Homeostasis and Hepatocarcinogenesis in Mice by Phosphorylating the Cell-Death Mediator Receptor-Interacting Protein Kinase 1

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The I?B-Kinase (IKK) complex-consisting of the catalytic subunits, IKK? and IKK?, as well as the regulatory subunit, NEMO-mediates activation of the nuclear factor ?B (NF-?B) pathway, but previous studies suggested the existence of NF-?B-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; IKK?/?(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 IKK? and IKK?-in addition to their known function in NF-?B activation-directly phosphorylate RIPK1 at distinct regions of the protein, thereby regulating cell viability. Loss of this IKK?/?-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).? 2016 by the American Association for the Study of Liver Diseases.
Original languageEnglish
Pages (from-to)1217-1231
JournalHepatology
Volume64
Issue number4
DOIs
Publication statusPublished - Oct 2016

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