A Non-canonical PDK1-RSK Signal Diminishes Pro-caspase-8-Mediated Necroptosis Blockade

  • Mol Cell. 2020 Oct 15;80(2):296-310.e6. doi: 10.1016/j.molcel.2020.09.004.
Zhang-Hua Yang  1 ,  Xiao-Nan Wu  2 ,  Peng He  1 ,  Xuekun Wang  1 ,  Jianfeng Wu  1 ,  Tingting Ai  1 ,  Chuan-Qi Zhong  1 ,  Xiurong Wu  1 ,  Yu Cong  1 ,  Rongfeng Zhu  1 ,  Hongda Li  1 ,  Zhi-Yu Cai  1 ,  Wei Mo  3 ,  Jiahuai Han  4
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 2. School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 3. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Research Unit of Cellular Stress of CAMS, Cancer Research Center of Xiamen University, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Research Unit of Cellular Stress of CAMS, Cancer Research Center of Xiamen University, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].
PMID: 32979304 DOI: 10.1016/j.molcel.2020.09.004
Abstract

Necroptosis induction in vitro often requires Caspase-8 (Casp8) inhibition by zVAD because pro-Casp8 cleaves RIP1 to disintegrate the necrosome. It has been unclear how the Casp8 blockade of Necroptosis is eliminated naturally. Here, we show that pro-Casp8 within the necrosome can be inactivated by phosphorylation at Thr265 (pC8T265). pC8T265 occurs in vitro in various necroptotic cells and in the cecum of TNF-treated mice. p90 RSK is the kinase of pro-Casp8. It is activated by a mechanism that does not need ERK but PDK1, which is recruited to the RIP1-RIP3-MLKL-containing necrosome. Phosphorylation of pro-Casp8 at Thr265 can substitute for zVAD to permit Necroptosis in vitro. pC8T265 mimic T265E knockin mice are embryonic lethal due to unconstrained Necroptosis, and the pharmaceutical inhibition of RSK-mediated pC8T265 diminishes TNF-induced cecum damage and lethality in mice by halting Necroptosis. Thus, phosphorylation of pro-Casp8 at Thr265 by RSK is an intrinsic mechanism for passing the Casp8 checkpoint of Necroptosis.

Keywords
PDK1; TNF; caspase-8; necroptosis; necrosome; p90 RSK; phosphorylation; zVAD.
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