title: Glycogen synthase kinase-3β stabilizes the interleukin (IL)-22 receptor from proteasomal degradation in murine lung epithelia.
abstract: Signaling through the interleukin (IL)-22 cytokine axis provides essential immune protection in the setting of extracellular infection as part of type 17 immunity. Molecular regulation of IL-22 receptor (IL-22R) protein levels is unknown. In murine lung epithelia, IL-22R is a relatively short-lived protein (t½ ∼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 display reduced phosphorylation levels and are more labile as compared with wild-type IL-22R when expressed in cells. 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.
authors.affiliation: From the Department of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Nathaniel M
authors.initials: NM
authors.lastname: Weathington
authors.affiliation: From the Department of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Snavely
authors.affiliation: From the Department of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
authors.affiliation: From the Department of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: From the Department of Medicine, the Acute Lung Injury Center of Excellence, and the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the Department of Medicine, the Acute Lung Injury Center of Excellence, and the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and the Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240 mallampallirk@upmc.edu.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016296:Mutagenesis; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D018123:Receptors, Interleukin; D025801:Ubiquitin; C415369:interleukin-22 receptor; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex
keywords: Cytokine; Glycogen Synthase Kinase 3 (GSK-3); Inflammation; Lung Injury; Protein Degradation
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