RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

Publication date: Available online 22 December 2016
Source:Cancer Cell
Author(s): Anne T. Schneider, Jérémie Gautheron, Maria Feoktistova, Christoph Roderburg, Sven H. Loosen, Sanchari Roy, Fabian Benz, Peter Schemmer, Markus W. Büchler, Ueli Nachbur, Ulf P. Neumann, Rene Tolba, Mark Luedde, Jessica Zucman-Rossi, Diana Panayotova-Dimitrova, Martin Leverkus, Christian Preisinger, Frank Tacke, Christian Trautwein, Thomas Longerich, Mihael Vucur, Tom Luedde
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.

Teaser

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.


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