Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis

Jiefei Geng, Yasushi Ito, Linyu Shi, Palak Amin, Jiachen Chu, Amanda Tomie Ouchida, Adnan Kasim Mookhtiar, Heng Zhao, Daichao Xu, Bing Shan, Ayaz Najafov, Guangping Gao, Shizuo Akira and Junying Yuan ()
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Jiefei Geng: Harvard Medical School
Yasushi Ito: Harvard Medical School
Linyu Shi: Chinese Academy of Sciences
Palak Amin: Harvard Medical School
Jiachen Chu: Harvard Medical School
Amanda Tomie Ouchida: Harvard Medical School
Adnan Kasim Mookhtiar: Harvard Medical School
Heng Zhao: Harvard Medical School
Daichao Xu: Harvard Medical School
Bing Shan: Chinese Academy of Sciences
Ayaz Najafov: Harvard Medical School
Guangping Gao: University of Massachusetts Medical School
Shizuo Akira: WPI Immunology Frontier Research Center (IFReC), Osaka University
Junying Yuan: Harvard Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00406-w

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