OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis
2019
Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of inflammatory pathologies. OTULIN is a
deubiquitinating enzymethat specifically cleaves linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC), and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. OTULIN was shown to negatively control NF-kB signaling in response to various stimuli, but also to protect cells from tumor necrosis factor (TNF)-induced apoptosis. To investigate the importance of OTULIN in liver homeostasis and pathology, we developed a novel mouse line specifically lacking OTULIN in liver parenchymal cells. These mice spontaneously develop a severe liver disease, characterized by liver inflammation,
hepatocyteapoptosis and compensatory
hepatocyteproliferation, leading to
steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated
death domain(
FADD) completely rescues the severe liver pathology, and knock-in expression of kinase inactive receptor-interacting protein kinase 1 (
RIPK1) significantly protects from developing liver disease, demonstrating that death receptor-mediated apoptosis of OTULIN-deficient
hepatocytestriggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease pathogenesis in
hepatocyte-specific OTULIN deficient mice. Together, our study reveals the critical importance of OTULIN in protecting
hepatocytesfrom death, and thereby avoid development of chronic liver inflammation and HCC in mice.
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