Cell fate determined by the activation balance between PKR and SPHK1

Double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) activation via autophosphorylation is the central cellular response to stress that promotes cell death or apoptosis. However, the key factors and mechanisms behind the simultaneous activation of pro-survival signaling pathways remain unkno...

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Bibliographic Details
Published in:Cell death and differentiation 2021-01, Vol.28 (1), p.401-418
Main Authors: Qiao, Han, Jiang, Tianqing, Mu, Peiqiang, Chen, Xiaoxuan, Wen, Xianhui, Hu, Zhangsheng, Tang, Shulin, Wen, Jikai, Deng, Yiqun
Format: Article
Language:English
Subjects:
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Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell death
Cell Differentiation - genetics
Cell fate
Cell Line
Cell Line, Tumor
Cellular stress response
Double-stranded RNA
eIF-2 kinase
eIF-2 Kinase - genetics
Endoplasmic reticulum
Endoplasmic Reticulum Stress - genetics
Homeostasis
Humans
Kinases
Life Sciences
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) - genetics
Protein kinase R
RNA, Double-Stranded - genetics
Signal Transduction
Sphingosine kinase
Stem Cells
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Summary:Double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) activation via autophosphorylation is the central cellular response to stress that promotes cell death or apoptosis. However, the key factors and mechanisms behind the simultaneous activation of pro-survival signaling pathways remain unknown. We have discovered a novel regulatory mechanism for the maintenance of cellular homeostasis that relies on the phosphorylation interplay between sphingosine kinase 1 (SPHK1) and PKR during exogenous stress. We identified SPHK1 as a previously unrecognized PKR substrate. Phosphorylated SPHK1, a central kinase, mediates the activation of PKR-induced pro-survival pathways by the S1P/S1PR1/MAPKs/IKKα signal axis, and antagonizes PKR-mediated endoplasmic reticulum (ER) stress signal transduction under stress conditions. Otherwise, phosphorylated SPHK1 also acts as the negative feedback factor, preferentially binding to the latent form of PKR at the C-terminal kinase motif, inhibiting the homodimerization of PKR, suppressing PKR autophosphorylation, and reducing the signaling strength for cell death and apoptosis. Our results suggest that the balance of the activation levels between PKR and SPHK1, a probable hallmark of homeostasis maintenance, determines cell fate during cellular stress response.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-020-00608-8