title: Focal adhesion kinase-mediated activation of glycogen synthase kinase 3β regulates IL-33 receptor internalization and IL-33 signaling.
abstract: IL-33, a relatively new member of the IL-1 cytokine family, plays a crucial role in allergic inflammation and acute lung injury. Long form ST2 (ST2L), the receptor for IL-33, is expressed on immune effector cells and lung epithelia and plays a critical role in triggering inflammation. We have previously shown that ST2L stability is regulated by the ubiquitin-proteasome system; however, its upstream internalization has not been studied. In this study, we demonstrate that glycogen synthase kinase 3β (GSK3β) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, and an effect was attenuated by inhibition or downregulation of GSK3β. GSK3β was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3β binding site mutant (ST2L(S446A)) and phosphorylation site mutant (ST2L(S442A)) are resistant to IL-33-induced ST2L internalization. We also found that IL-33 activated focal adhesion kinase (FAK). Inhibition of FAK impaired IL-33-induced GSK3β activation and ST2L internalization. Furthermore, inhibition of ST2L internalization enhanced IL-33-induced cytokine release in lung epithelial cells. These results suggest that modulation of the ST2L internalization by FAK/GSK3β might serve as a unique strategy to lessen pulmonary inflammation.
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Bowser
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Traister
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Fan
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 zhaoy3@upmc.edu.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000276:immunology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000276:immunology*; D000071679:Glycogen Synthase Kinase 3 beta; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D020125:Mutation, Missense; D011485:Protein Binding; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D017472:Receptors, Interleukin-1; C530318:ST2L protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3