Glycogen synthase kinase {beta} stabilizes the IL-22 receptor from proteasomal degradation in murine lung epithelia [Immunology]

April 17th, 2014 by Weathington, N. M., Snavely, C. A., Chen, B. B., Zhao, J., Zhao, Y., Mallampalli, R. K.

Signaling through the interleukin (IL)-22 cytokine axis provides essential immune protection in the setting of extracellular infection as part of the immunobiology of the Th17 effector cell subset. Molecular regulation of IL-22 receptor (IL-22R) protein levels is unknown. In murine lung epithelia IL-22R is a relatively short-lived protein (half life ~1.5 h) degraded by the ubiquitin proteasome under normal unstimulated conditions but its degradation is accelerated by IL-22 treatment. Lys 449 within the intracellular C-terminal domain of the IL-22R serves as a ubiquitin acceptor site as disruption of this site by deletion or site directed mutagenesis creates an IL-22R variant that when expressed in cells is degradation resistant and not ubiquitinated. Glycogen synthase kinase (GSK)-3β phosphorylates the IL-22R within a consensus phosphorylation signature at Ser 410 and Ser 414 and IL-22 treatment of cells triggers GSK-3β inactivation. GSK-3β overexpression results in accumulation of IL-22R protein whereas GSK-3β depletion in cells reduces levels of the receptor. Mutagenesis of IL-22R at Ser 410 and Ser 414 results in receptor variants that when expressed in cells display reduced phosphorylation levels and are more labile compared to wild- type IL-22R. Further, the cytoskeletal protein cortactin, which is important for epithelial spreading and barrier formation, is phosphorylated and activated at the epithelial cell leading edge after treatment with IL-22, but this effect is reduced after GSK-3β knockdown. These findings reveal the ability of GSK-3β to modulate IL-22R protein stability that might have significant implications for cytoprotective functions and therapeutic targeting of the IL-22 signaling axis