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A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes prostaglandin2ainduced corpus luteum regression.

Authors :
Dianrong Li
Jie Chen
Jia Guo
Lin Li
Gaihong Cai
She Chen
Jia Huang
Hui Yang
Yinhua Zhuang
Fengchao Wang
Xiaodong Wang
Source :
eLife. 5/24/2021, p1-29. 29p.
Publication Year :
2021

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 PGF2a 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 PGF2a 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
2050084X
Database :
Academic Search Index
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
152085510
Full Text :
https://doi.org/10.7554/eLife.67409