C-terminal domain of c-FLIPL inhibits the interaction of caspase-8 prodomain with RIP1 death domain and regulates caspase-8-dependent NF-{kappa}B activation [Signal Transduction]
January 6th, 2014 by Matsuda, I., Matsuo, K., Matsushita, Y., Haruna, Y., Niwa, M., Kataoka, T.
Caspase-8 plays an essential role in the regulation of apoptotic and non-apoptotic signaling pathways. The long form of the caspase-8 modulator cellular FLIP (c-FLIPL) was previously shown to regulate caspase-8-dependent NF-κB activation by receptor-interacting protein 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). In this study the molecular mechanism by which c-FLIPL regulates caspase-8-dependent NF-κB activation was further explored in the human embryonic kidney cell line HEK 293 and variant cells barely expressing caspase-8. The caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone greatly diminished caspase-8-dependent NF-κB activation induced by Fas ligand when c-FLIPL, but not its N-terminal fragment c-FLIP(p43) was expressed. The prodomain of caspase-8 was found to interact with the RIP1 death domain and to be sufficient to mediate NF-κB activation induced by FasL or c-FLIP(p43). The interaction of the RIP1 death domain with caspase-8 was inhibited by c-FLIPL, but not c-FLIP(p43). Thus, these results reveal that the C-terminal domain of c-FLIPL specifically inhibits the interaction of the caspase-8 prodomain with the RIP1 death domain and thereby regulates caspase-8-dependent NF-κB activation.