RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

• Published in: Cancer cell Vol. 31; no. 1; pp. 94 - 109
• Main Authors: Schneider, Anne T., Gautheron, Jérémie, Feoktistova, Maria, Roderburg, Christoph, Loosen, Sven H., Roy, Sanchari, Benz, Fabian, Schemmer, Peter, Büchler, Markus W., Nachbur, Ueli, Neumann, Ulf P., Tolba, Rene, Luedde, Mark, Zucman-Rossi, Jessica, Panayotova-Dimitrova, Diana, Leverkus, Martin, Preisinger, Christian, Tacke, Frank, Trautwein, Christian, Longerich, Thomas, Vucur, Mihael, Luedde, Tom
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.01.2017; Elsevier
• Subjects: Animals; apoptosis; Caspase 8 - metabolism; caspase-8; cIAP-1; HCC; hepatocarcinogenesis; Hepatocytes - physiology; Humans; Life Sciences; Liver Neoplasms - etiology; Liver Neoplasms - prevention & control; Male; Mice; Mice, Inbred C57BL; necroptosis; NF-kappa B - physiology; NF-κB; Proteasome Endopeptidase Complex - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - physiology; RIP1; RIP3; RIPK3; TNF Receptor-Associated Factor 2 - physiology; Tumor Necrosis Factor-alpha - pharmacology; NF-κB; caspase-8; RIPK3; apoptosis; HCC; cIAP-1; hepatocarcinogenesis; RIP3; RIP1; necroptosis; Caspase-8; NF-kappaB; RIP1 RIP3 RIPK3 cIAP-1 Caspase-8 NF-kappaB necroptosis apoptosis HCC hepatocarcinogenesis
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2016.11.009

Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis. •RIPK1 ablation induces TNF-mediated hepatocyte apoptosis without affecting NF-κB•Loss of RIPK1 leads to proteasomal TRAF2 degradation in a kinase-independent manner•RIPK1 and TRAF2 act together to prevent spontaneous HCC development•Low expression of TRAF2 and RIPK1 in human HCC predicts poor prognosis Schneider et al. show that RIPK1 deficiency in liver parenchymal cells (LPC) enhances TNF-induced TRAF2 degradation, leading to liver injury. Loss of both RIPK1 and TRAF2 in LPC promotes hepatocellular carcinoma (HCC) development. In human HCC, low RIPK1 and TRAF2 expression is associated with poor outcome.