title: SCFFBXO17E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia.
abstract: Glycogen synthase kinase-3β (GSK3β) has diverse biological roles including effects on cellular differentiation, migration, and inflammation. GSK3β phosphorylates proteins to generate phosphodegrons necessary for recognition by Skp1/Cullin-1/F-box (SCF) E3 ubiquitin ligases leading to subsequent proteasomal degradation of these substrates. However, little is known regarding how GSK3β protein stability itself is regulated and how its stability may influence inflammation. Here we show that GSK3β is degraded by the ubiquitin-proteasome pathway in murine lung epithelial cells through lysine 183 as an acceptor site for K48 polyubiquitination. We have identified FBXO17 as an F-box protein subunit that recognizes and mediates GSK3β polyubiquitination. Both endogenous and ectopically expressedFBXO17associate with GSK3β, and its overexpression leads to decreased protein levels of GSK3β. SilencingFBXO17gene expression increased the half-life of GSK3β in cells. Furthermore, overexpression ofFBXO17inhibits agonist-induced release of keratinocyte-derived cytokine (KC) and interleukin-6 (IL-6) production by cells. Thus, the SCFFBXO17E3 ubiquitin ligase complex negatively regulates inflammation by targeting GSK3β in lung epithelia.
authors.affiliation: From the Departments of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Tomeka
authors.initials: T
authors.lastname: Suber
authors.affiliation: From the Departments of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wei
authors.affiliation: From the Departments of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Anastasia M
authors.initials: AM
authors.lastname: Jacko
authors.affiliation: From the Departments of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Ina
authors.initials: I
authors.lastname: Nikolli
authors.affiliation: From the Departments of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the Departments of Medicine, the Acute Lung Injury Center of Excellence, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: From the Departments of Medicine, the Acute Lung Injury Center of Excellence, and mallampallirk@upmc.edu.|Cell Biology, Physiology, and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and.|the Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
mesh_terms: D000818:Animals; D002460:Cell Line; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D020545:Respiratory Mucosa / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: E3 ubiquitin ligase; inflammation; lung; lung injury; ubiquitin