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

• DOI: 10.1016/j.molcel.2020.09.004
• Publication Date: 2020-09-25T14:43:06Z
• Authors: Zhang-Hua Yang; Xiao-Nan Wu; Peng He; Xuekun Wang; Jianfeng Wu; Tingting Ai; Chuan-Qi Zhong; Xiurong Wu; Yu Cong; Rongfeng Zhu; Hongda Li; Zhi-Yu Cai; Wei Mo; Jiahuai Han
• Keywords: 0301 basic medicine; Caspase 8; Tumor Necrosis Factor-alpha; Embryonic Development; Embryo, Mammalian; Ribosomal Protein S6 Kinases, 90-kDa; Cell Line; 3. Good health; 3-Phosphoinositide-Dependent Protein Kinases; Mice, Inbred C57BL; 03 medical and health sciences; Phosphothreonine; Organ Specificity; Mutation; Necroptosis; Animals; Humans; Phosphorylation; Extracellular Signal-Regulated MAP Kinases; Cecum; Protein Kinases; Signal Transduction

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.