Interleukin 22 receptor abundance and signaling is regulated by the ubiquitin proteasome and glycogen synthase kinase 3β. (INM2P.422)

Abstract

Abstract Signaling through the interleukin (IL)-22 cytokine axis provides essential immune protection in the setting of extracellular infection at mucosal and other epithelial surfaces. Molecular regulation of IL-22 receptor (IL-22R) protein has not been characterized. In mouse lung epithelia, IL-22R is expressed as a relatively short-lived protein and is degraded by the ubiquitin proteasome. Its degradation is accelerated when cells are stimulated by IL-22. Lys 449 within the intracellular C-terminal domain of the IL-22R serves as a ubiquitin acceptor site for proteasomal degradation as deletion or mutation of K449 creates a degradation resistant IL-22R mutant protein that is not ubiquitinated in cells. IL-22 treatment of cells triggers glycogen synthase kinase (GSK)-3β inactivation, and GSK-3β phosphorylates the IL-22R within a consensus phosphorylation signature at Ser 410. GSK-3β overexpression results in accumulation of IL-22R protein while GSK-3β depletion in cells reduces levels of the receptor, and this effect is abolished on mutation of the 410-414 phosphorylation domain. Signal transduction of IL-22 appears increased when GSK-3β is overexpressed. This study shows GSK-3β as a modulator of IL-22R protein stability, which may be important for host defense and could impact therapeutic targeting of the IL-22 signaling axis.