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TRADD mediates the tumor necrosis factor-induced apoptosis of L929 cells in the absence of RIP3.

ABSTRACT: Receptor-interacting protein kinase 3 (RIP3) is a critical initiator in mediating necroptosis induced by tumor necrosis factor alpha (TNF?) in L929 cells, so knockdown of RIP3 inhibits TNF?-induced L929 cell necroptosis. However, RIP3 knockdown was shown to switch TNF?-induced necroptosis to apoptosis in L929 cells in other studies. Therefore, whether RIP3 knockdown blocks the TNF?-induced death of L929 cells is controversial. In this study, TNF? activated caspase pathway and induced cell death in RIP3 knockdown L929 cells, and the RIP3-independent cell death had been blocked by Z-VAD-FMK (pan-caspase inhibitor) or caspase 8 knockdown, demonstrating that RIP3 knockdown switched TNF?-induced necroptosis to caspase-dependent apoptosis. Although both TNF receptor type 1-associated death domain protein (TRADD) and RIP1 have been reported to mediate TNF?-induced apoptosis, the knockdown of TRADD, but not RIP1, suppressed TNF?-induced activation of the caspase pathway and subsequent apoptosis in RIP3 knockdown L929 cells. In addition, TRADD bound and activated caspase 8 during the RIP3-independent apoptosis process, indicating that TRADD initiates RIP3-independent apoptosis by activating the caspase pathway. Collectively, we identified the target and mechanism underlying RIP3-independent apoptosis and elucidated the coordinated roles of RIP3 and TRADD in mediating the programmed cell death of L929 cells following TNF? stimulation.


PROVIDER: S-EPMC5701027 | BioStudies | 2017-01-01T00:00:00Z

REPOSITORIES: biostudies

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