A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes prostaglandin2α-induced corpus luteum regression

Dianrong Li; Jie Chen; Jia Guo; Lin Li; Gaihong Cai; She Chen; Jia Huang; Hui Yang; Yinhua Zhuang; Fengchao Wang; Xiaodong Wang

doi:10.7554/eLife.67409

A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes prostaglandin_2α-induced corpus luteum regression

Elife. 2021 May 24:10:e67409. doi: 10.7554/eLife.67409.

Authors

Dianrong Li^{1

2}, Jie Chen^{1

2}, Jia Guo^{1

2}, Lin Li^{1

2}, Gaihong Cai^{1

2}, She Chen^{1

2}, Jia Huang³, Hui Yang³, Yinhua Zhuang^{1

2}, Fengchao Wang^{1

2}, Xiaodong Wang^{1

2}

Affiliations

¹ National Institute of Biological Sciences, Beijing, China.
² Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
³ 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.

Abstract

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 PGF_2α 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 PGF_2α 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.

Keywords: Caspase-8; RIPK3; apoptosis; cell biology; mouse; necroptosis; ovary; prostaglandins.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Chaperonins / genetics
Chaperonins / metabolism
Corpus Luteum / enzymology*
Corpus Luteum / pathology
Dinoprost / metabolism*
Fas-Associated Death Domain Protein / genetics
Fas-Associated Death Domain Protein / metabolism
Female
HEK293 Cells
HT29 Cells
HeLa Cells
Humans
MCF-7 Cells
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Chaperones / genetics
Molecular Chaperones / metabolism
Mutation
Phosphorylation
Protein Kinases / genetics
Protein Kinases / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
Signal Transduction

Substances

CDC37 protein, human
Cdc37 protein, mouse
Cell Cycle Proteins
FADD protein, human
Fadd protein, mouse
Fas-Associated Death Domain Protein
Molecular Chaperones
Dinoprost
MLKL protein, human
MLKL protein, mouse
Protein Kinases
RIPK3 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk3 protein, mouse
Chaperonins

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.