Abstract
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.
Highlights
There is an equilibrium between the net growth rate and the net death rate of cells, but this physiologicalEdited by R
DON exposure significantly increased the phosphorylation of protein kinase R (PKR) and sphingosine kinase 1 (SPHK1) over a broad timerange, and SPHK1 phosphorylation presented a lag effect compared with phosphorylated PKR in both cell lines (Fig. 1a and Supplementary Fig. 2)
We observed similar activation effects in the UVC-irradiated, TNF-α and LPStreated cells (Fig. 1b). These results suggest that the typical ribotoxic stress response (RSR) inducers induce the phosphorylation of SPHK1, which reveals a novel underlying stress-sensitive function of SPHK1
Summary
There is an equilibrium between the net growth rate and the net death rate of cells, but this physiological. Several cellular or viral proteins have been identified that are able to inhibit PKR kinase activity, either by direct interaction, or by competitively binding to PKR activators or substrates [14,15,16,17,18]. Phosphorylated SPHK1 preferentially binds to latent PKR, and negates PKR further activation during stress response This attenuates the IRE1α-dependent endoplasmic reticulum (ER) stress process, and protects cells from stress-induced cell death or apoptosis. Our results confirm the mutual interplay between the two kinases—especially with regard to activation and negative feedback—during cellular stress response They reveal that cell fate is probably determined by newly built homeostasis during stress stimuli via self-balance in the phosphorylation levels of SPHK1 and PKR
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