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IκB kinaseα/β control biliary homeostasis and hepatocarcinogenesis in mice by phosphorylating the cell-death mediator receptor-interacting protein kinase 1.
Hepatology 64, 1217-1231 (2016)
The IκB-Kinase (IKK) complex - consisting of the catalytic subunits IKKα and IKKβ as well as the regulatory subunit NEMO - mediates activation of the 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 (LPC) (IKKα/β(LPC-KO) ) were intercrossed with RIPK1(LPC-KO) or RIPK3(-/-) mice to examine if 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 LPC inhibits compensatory proliferation of hepatocytes and intrahepatic biliary cells, thus impeding HCC development but promoting biliary cell paucity and lethal cholestasis. CONCLUSIONS: Collectively, these findings show that IKK-complex subunits transmits 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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cholestasis ; Inflammation ; Liver Cancer ; Programmed Cell-death ; Proliferation; Hepatocellular-carcinoma; Ikk-alpha; Programmed Necrosis; Rip1 Kinase; Tnf-alpha; Cancer; Liver; Activation; Apoptosis; Proliferation
Language
english
Publication Year
2016
HGF-reported in Year
2016
ISSN (print) / ISBN
0270-9139
e-ISSN
1527-3350
Journal
Hepatology
Quellenangaben
Volume: 64,
Issue: 4,
Pages: 1217-1231
Publisher
Wiley
Publishing Place
Hoboken, NJ
Reviewing status
Peer reviewed
Institute(s)
Institute of Virology (VIRO)
POF-Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s)
Immune Response and Infection
PSP Element(s)
G-551600-001
WOS ID
WOS:000384552300020
PubMed ID
27396433
Erfassungsdatum
2016-07-13