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

C Koppe, P Verheugd, J Gautheron, F Reisinger… - …, 2016 - Wiley Online Library
C Koppe, P Verheugd, J Gautheron, F Reisinger, K Kreggenwinkel, C Roderburg…
Hepatology, 2016Wiley Online Library
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 …
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)
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