IL-37-induced activation of glycogen synthase kinase 3? promotes IL-1R8/Sigirr phosphorylation, internalization, and degradation in lung epithelial cells.

Interleukin (IL)-37 diminishes a variety of inflammatory responses through ligation to its receptor IL-1R8/Sigirr. Sigirr is a Toll like receptor/IL-1R family member. We have shown that Sigirr is not stable in response to IL-37 treatment. IL-37-induced Sigirr degradation is mediated by the ubiquitin-proteasome system, and the process is reversed by ...
a deubiquitinase, USP13. However, the molecular mechanisms by which USP13 regulates Sigirr stability have not been revealed. In this study, we investigate the roles of glycogen synthesis kinase 3? (GSK3?) in Sigirr phosphorylation and stability. IL-37 stimulation induced Sigirr phosphorylation and degradation, as well as activation of GSK3?. Inhibition of GSK3? attenuated IL-37-induced Sigirr phosphorylation, while exogenous expressed GSK3? promoted Sigirr phosphorylation at threonine (T)372 residue. Sigirr association with GSK3? was detected. Amino acid residues 51-101 in GSK3? were identified as the Sigirr binding domain. These data indicate that GSK3? mediates IL-37-induced threonine phosphorylation of Sigirr. Further, we investigated the role of GSK3?-mediated phosphorylation of Sigirr in Sigirr degradation. Inhibition of GSK3? attenuated IL-37-induced Sigirr degradation, while T372 mutant of Sigirr was resistant to IL-37-mediated degradation. Furthermore, inhibition of Sigirr phosphorylation prevented Sigirr internalization and association with USP13, suggesting GSK3? promotes Sigirr degradation through disrupting Sigirr association with USP13.
Mesh Terms:
Animals, Cells, Cultured, Epithelial Cells, Glycogen Synthase Kinase 3 beta, Humans, Interleukin-1, Lung, Mice, Phosphorylation, Proteasome Endopeptidase Complex, Receptors, Interleukin-1, Signal Transduction, Toll-Like Receptors
J Cell Physiol
Date: Dec. 01, 2020
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