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; Junying Yuan

doi:10.1038/s41467-017-00406-w

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, Junying Yuan

Research output: Contribution to journal › Article › peer-review

175 Scopus citations

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.

Original language	English (US)
Article number	359
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00406-w
State	Published - Dec 1 2017
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis",

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.",

author = "Jiefei Geng and Yasushi Ito and Linyu Shi and Palak Amin and Jiachen Chu and Ouchida, {Amanda Tomie} and Mookhtiar, {Adnan Kasim} and Heng Zhao and Daichao Xu and Bing Shan and Ayaz Najafov and Guangping Gao and Shizuo Akira and Junying Yuan",

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doi = "10.1038/s41467-017-00406-w",

language = "English (US)",

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T1 - Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis

AU - Geng, Jiefei

AU - Ito, Yasushi

AU - Shi, Linyu

AU - Amin, Palak

AU - Chu, Jiachen

AU - Ouchida, Amanda Tomie

AU - Mookhtiar, Adnan Kasim

AU - Zhao, Heng

AU - Xu, Daichao

AU - Shan, Bing

AU - Najafov, Ayaz

AU - Gao, Guangping

AU - Akira, Shizuo

AU - Yuan, Junying

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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

Abstract

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