title: NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis.
abstract: IκB kinase/nuclear [corrected] factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-κB-dependent and -independent functions.
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.
authors.forename: Vangelis
authors.initials: V
authors.lastname: Kondylis
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Polykratis
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Ehlken
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Ochoa-Callejero
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, INF 224, 69120 Heidelberg, Germany.
authors.forename: Beate Katharina
authors.initials: BK
authors.lastname: Straub
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.
authors.forename: Santosh
authors.initials: S
authors.lastname: Krishna-Subramanian
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.
authors.forename: Trieu-My
authors.initials: TM
authors.lastname: Van
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.
authors.forename: Harald-Morten
authors.initials: HM
authors.lastname: Curth
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Heise
authors.affiliation: Leibniz-Institute for Age Research-Fritz-Lipmann-Institute, 07745 Jena, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Weih
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, INF 224, 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Molecular, Cellular and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kelliher
authors.affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany. Electronic address: pasparakis@uni-koeln.de.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse