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Amin, Palak

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Amin, Palak

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    Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis
    (Nature Publishing Group UK, 2017) Geng, Jiefei; Ito, Yasushi; Shi, Linyu; Amin, Palak; Chu, Jiachen; Ouchida, Amanda Tomie; Mookhtiar, Adnan Kasim; Zhao, Heng; Xu, Daichao; Shan, Bing; Najafov, Ayaz; Gao, Guangping; Akira, Shizuo; Yuan, Junying
    Stimulation 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.