Geng, JiefeiIto, YasushiShi, LinyuAmin, PalakChu, JiachenOuchida, Amanda TomieMookhtiar, Adnan KasimZhao, HengXu, DaichaoShan, BingNajafov, AyazGao, GuangpingAkira, ShizuoYuan, Junying2017-12-052017Geng, J., Y. Ito, L. Shi, P. Amin, J. Chu, A. T. Ouchida, A. K. Mookhtiar, et al. 2017. “Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis.” Nature Communications 8 (1): 359. doi:10.1038/s41467-017-00406-w. http://dx.doi.org/10.1038/s41467-017-00406-w.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34491927Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.en-USJournal Article2017-12-0510.1038/s41467-017-00406-w