TY - JOUR
T1 - I kappa B Kinase alpha/beta Control Biliary Homeostasis and Hepatocarcinogenesis in Mice by Phosphorylating the Cell-Death Mediator Receptor-Interacting Protein Kinase 1
AU - Koppe, Christiane
AU - Verheugd, Patricia
AU - Gautheron, Jeremie
AU - Reisinger, Florian
AU - Kreggenwinkel, Karina
AU - Roderburg, Christoph
AU - Quagliata, Luca
AU - Terracciano, Luigi
AU - Gassler, Nikolaus
AU - Tolba, Rene H.
AU - Boege, Yannick
AU - Weber, Achim
AU - Karin, Michael
AU - Luedde, Mark
AU - Neumann, Ulf P.
AU - Weiskirchen, Ralf
AU - Tacke, Frank
AU - Vucur, Mihael
AU - Trautwein, Christian
AU - Luescher, Bernhard
AU - Preisinger, Christian
AU - Heikenwalder, Mathias
AU - Luedde, Tom
PY - 2016/10
Y1 - 2016/10
N2 - 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.
AB - 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.
U2 - 10.1002/hep.28723
DO - 10.1002/hep.28723
M3 - Article
C2 - 27396433
SN - 0270-9139
VL - 64
SP - 1217
EP - 1231
JO - Hepatology
JF - Hepatology
IS - 4
ER -