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bioRxiv · 10.1101/2021.02.14.431152

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

Li, D.·Chen, J.·Guo, J.·Li, L.·Cai, G.·Chen, S.·Huang, J.·Yang, H.·Zhuang, Y.·Wang, F.·Wang, X.
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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 PGF2 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 PGF2 but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knockin 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.

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Li, D., Chen, J., Guo, J., Li, L., Cai, G., Chen, S., Huang, J., Yang, H., Zhuang, Y., Wang, F., Wang, X.. 2021-02-15. A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes corpus luteum regression. https://doi.org/10.1101/2021.02.14.431152

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