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OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis.

Authors
  • Verboom, Lien1
  • Martens, Arne1
  • Priem, Dario1
  • Hoste, Esther1
  • Sze, Mozes1
  • Vikkula, Hanna1
  • Van Hove, Lisette1
  • Voet, Sofie1
  • Roels, Jana2
  • Maelfait, Jonathan1
  • Bongiovanni, Laura3
  • de Bruin, Alain3
  • Scott, Charlotte L1
  • Saeys, Yvan2
  • Pasparakis, Manolis4
  • Bertrand, Mathieu J M1
  • van Loo, Geert5
  • 1 VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. , (Belgium)
  • 2 VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Applied Mathematics, Computer Sciences, and Statistics, Ghent University, 9052 Ghent, Belgium. , (Belgium)
  • 3 Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584, the Netherlands; Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen 9713, the Netherlands. , (Netherlands)
  • 4 Institute for Genetics, Centre for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. , (Germany)
  • 5 VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. Electronic address: [email protected] , (Belgium)
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Feb 18, 2020
Volume
30
Issue
7
Identifiers
DOI: 10.1016/j.celrep.2020.01.028
PMID: 32075762
Source
Medline
Language
English
License
Unknown

Abstract

Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of disease. OTULIN is a deubiquitinating enzyme that controls inflammation by cleaving linear ubiquitin chains generated by the linear ubiquitin chain assembly complex. Here, we show that ablation of OTULIN in liver parenchymal cells in mice causes severe liver disease which is characterized by liver inflammation, hepatocyte apoptosis, and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues and knockin expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects mice from developing liver disease, demonstrating that apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease in hepatocyte-specific OTULIN-deficient mice. Our study reveals the critical importance of OTULIN in protecting hepatocytes from death, thereby preventing the development of chronic liver inflammation and HCC. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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