Abstract
Linear ubiquitination is a key posttranslational modification that regulates immune signaling and cell death pathways, notably tumor necrosis factor receptor 1 (TNFR1) signaling. The only known enzyme complex capable of forming linear ubiquitin chains under native conditions to date is the linear ubiquitin chain assembly complex, of which the catalytic core component is heme‐oxidized iron regulatory protein 2 ubiquitin ligase‐1–interacting protein (HOIP). To understand the underlying mechanisms of maintenance of liver homeostasis and the role of linear ubiquitination specifically in liver parenchymal cells, we investigated the physiological role of HOIP in the liver parenchyma. To do so, we created mice harboring liver parenchymal cell–specific deletion of HOIP (HoipΔhep mice) by crossing Hoip‐floxed mice with albumin–Cre mice. HOIP deficiency in liver parenchymal cells triggered tumorigenesis at 18 months of age preceded by spontaneous hepatocyte apoptosis and liver inflammation within the first month of life. In line with the emergence of inflammation, HoipΔhep mice displayed enhanced liver regeneration and DNA damage. In addition, consistent with increased apoptosis, HOIP‐deficient hepatocytes showed enhanced caspase activation and endogenous formation of a death‐inducing signaling complex which activated caspase‐8. Unexpectedly, exacerbated caspase activation and apoptosis were not dependent on TNFR1, whereas ensuing liver inflammation and tumorigenesis were promoted by TNFR1 signaling. Conclusion: The linear ubiquitin chain assembly complex serves as a previously undescribed tumor suppressor in the liver, restraining TNFR1‐independent apoptosis in hepatocytes which, in its absence, is causative of TNFR1‐mediated inflammation, resulting in hepatocarcinogenesis. (Hepatology 2017;65:1963‐1978).
Highlights
IntroductionHEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases
Liver parenchymal cell (LPC)–specific IjB kinase (IKK) b–deficient mice are more susceptible to diethylnitrosamine-induced cell death and carcinogenesis.[8]. Follow-up studies employing LPCspecific nuclear factor-jB (NF-jB) essential modulator (NEMO) and transforming growth factor b–activated kinase 1 (TAK1) knockout (KO) mice indicated that optimal regulation of TNF receptor 1 (TNFR1) signaling is crucial to maintain liver homeostasis and to protect from inflammation and cancer.[9,10] Importantly, in addition to the regulation of NF-jB, aberrant activation of cell death machineries triggered by deregulated TNFR1 signaling can evoke severe liver pathology
Hepatocyte apoptosis and hepatocarcinogenesis due to liver parenchymal cell (LPC)-specific TAK1 deficiency are mediated by caspase-8 in those cells, while cholestasis was induced by the necroptosis inducer receptor–interacting protein kinase (RIPK3).(11) transforming growth factor b–activated kinase 1 and the IKKa–IKKb– nuclear factor-jB essential modulator (NEMO) complex have been shown to suppress cell death signaling independently of their role in activating NF-jB in hepatocytes and other cell types.[12,13] deregulated cell death and/or NF-jB signaling in hepatocytes can result in liver inflammation and carcinogenesis
Summary
HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases Liver parenchymal cell (LPC)–specific IjB kinase (IKK) b–deficient mice are more susceptible to diethylnitrosamine-induced cell death and carcinogenesis.[8] Follow-up studies employing LPCspecific nuclear factor-jB (NF-jB) essential modulator (NEMO) and transforming growth factor b–activated kinase 1 (TAK1) knockout (KO) mice indicated that optimal regulation of TNFR1 signaling is crucial to maintain liver homeostasis and to protect from inflammation and cancer.[9,10] Importantly, in addition to the regulation of NF-jB, aberrant activation of cell death machineries triggered by deregulated TNFR1 signaling can evoke severe liver pathology.
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