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RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome

Author

Listed:
  • Yingying Zhang

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Sheng Sean Su

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Shubo Zhao

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Zhentao Yang

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Chuan-Qi Zhong

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Xin Chen

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Qixu Cai

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Zhang-Hua Yang

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Deli Huang

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Rui Wu

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Jiahuai Han

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

Abstract

Necroptosis is a type of programmed cell death with great significance in many pathological processes. Tumour necrosis factor-α(TNF), a proinflammatory cytokine, is a prototypic trigger of necroptosis. It is known that mitochondrial reactive oxygen species (ROS) promote necroptosis, and that kinase activity of receptor interacting protein 1 (RIP1) is required for TNF-induced necroptosis. However, how ROS function and what RIP1 phosphorylates to promote necroptosis are largely unknown. Here we show that three crucial cysteines in RIP1 are required for sensing ROS, and ROS subsequently activates RIP1 autophosphorylation on serine residue 161 (S161). The major function of RIP1 kinase activity in TNF-induced necroptosis is to autophosphorylate S161. This specific phosphorylation then enables RIP1 to recruit RIP3 and form a functional necrosome, a central controller of necroptosis. Since ROS induction is known to require necrosomal RIP3, ROS therefore function in a positive feedback circuit that ensures effective induction of necroptosis.

Suggested Citation

  • Yingying Zhang & Sheng Sean Su & Shubo Zhao & Zhentao Yang & Chuan-Qi Zhong & Xin Chen & Qixu Cai & Zhang-Hua Yang & Deli Huang & Rui Wu & Jiahuai Han, 2017. "RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14329
    DOI: 10.1038/ncomms14329
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    Cited by:

    1. Hang Zhou & Wenjun Wang & Hairong Xu & Yong Liang & Jiyu Ding & Mengjie Lv & Boyang Ren & Hua Peng & Yang-Xin Fu & Mingzhao Zhu, 2024. "Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Jingchun Du & Yougui Xiang & Hua Liu & Shuzhen Liu & Ashwani Kumar & Chao Xing & Zhigao Wang, 2021. "RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Fay Newton & Mihail Halachev & Linda Nguyen & Lisa McKie & Pleasantine Mill & Roly Megaw, 2025. "Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    4. Xuhang Wang & Yuhan Zhang & Xinru Chen & Kailai Fu & Jiaqi Cui & Jiaoling Wu & Yu Sun & Jianluan Ren & Feng Xue & Jianjun Dai & Fang Tang, 2025. "RIPK1 kinase drove brain microvascular endothelial cells death and blood-brain barrier disruption in neonatal Escherichia coli meningitis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    5. Mark W. Youngblood & Shashwat Tripathi & Hinda Najem & Harrshavasan Congivaram & Mateo Gomez & Thomas K. Sears & Lisa Hurley & Leah K. Billingham & Caylee Silvers & Wenxia Wang & Deanna Tiek & Nishant, 2026. "STING activation induces cytotoxic and immune responses in meningiomas via inflammatory cell death pathways," Nature Communications, Nature, vol. 17(1), pages 1-19, December.

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