AUTHOR=Wang Lili , Chang Xixi , Feng Jinli , Yu Jiyun , Chen Guozhu 

TITLE=TRADD Mediates RIPK1-Independent Necroptosis Induced by Tumor Necrosis Factor

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 7 - 2019

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2019.00393

DOI=10.3389/fcell.2019.00393

ISSN=2296-634X

ABSTRACT=As a regulated form of programmed cell death, necroptosis has the intrinsic initiators, including receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which combine to form necroptotic signaling pathway and mediate necroptosis induced by various necroptotic stimuli, including tumor necrosis factor (TNF). Although chemical inhibition of RIPK1 blocks TNF-induced necroptosis, genetic elimination of RIPK1 does not suppress but facilitate necroptosis triggered by TNF. Moreover, RIPK3 has been reported to mediate the RIPK1-independent necroptosis, but the involved mechanism is unclear. In this study, we found that TRADD was essential for TNF-induced necroptosis in RIPK1-knockdown L929 cells. Mechanistic study demonstrated that TRADD bound RIPK3 to form new protein complex, which then promoted RIPK3 phosphorylation via facilitating RIPK3 oligomerization, leading to RIPK3-MLKL signaling pathway activation. Therefore, TRADD acted as a partner of RIPK3 to initiate necroptosis in RIPK1-knockdown L929 cells in response to TNF stimulation. In addition, TRADD was critical for the accumulation of reactive oxygen species, which contributed to RIPK1-independent necroptosis triggered by TNF. Collectively, our data demonstrate that TRADD acts as the new target protein for TNF-induced RIPK3 activation and the RIPK1-indepdentdent necroptosis.