National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
Jie Chen
National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
Jia Guo
National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
Lin Li
National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
Gaihong Cai
National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
She Chen
National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
Jia Huang
Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Hui Yang
Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Yinhua Zhuang
National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
Fengchao Wang
National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) normally signals to necroptosis by phosphorylating MLKL. We report here that when the cellular RIPK3 chaperone Hsp90/CDC37 level is low, RIPK3 also signals to apoptosis. The apoptotic function of RIPK3 requires phosphorylation of the serine 165/threonine 166 sites on its kinase activation loop, resulting in inactivation of RIPK3 kinase activity while gaining the ability to recruit RIPK1, FADD, and caspase-8 to form a cytosolic caspase-activating complex, thereby triggering apoptosis. We found that PGF2α induces RIPK3 expression in luteal granulosa cells in the ovary to cause luteal regression through this RIPK3-mediated apoptosis pathway. Mice carrying homozygous phosphorylation-resistant RIPK3 S165A/T166A knockin mutations failed to respond to PGF2α but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knock-in mutation underwent spontaneous apoptosis in multiple RIPK3-expressing tissues and died shortly after birth. Thus, RIPK3 signals to either necroptosis or apoptosis depending on its serine 165/threonine 166 phosphorylation status.
