Focal Adhesion Kinase–Mediated Activation of Glycogen Synthase Kinase 3β Regulates IL-33 Receptor Internalization and IL-33 Signaling
Copyright policy )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 (ST2LS446A) and phosphorylation site mutant (ST2LS442A) 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.
- UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- University of Pittsburgh United States
- University of Pittsburgh School of Medicine United States
- University of Pittsburgh School of Medicine United States
Binding Sites, Glycogen Synthase Kinase 3 beta, Interleukins, Mutation, Missense, Receptors, Interleukin-1, Interleukin-33, Cell Line, Enzyme Activation, Glycogen Synthase Kinase 3, Mice, Amino Acid Substitution, Focal Adhesion Kinase 1, Animals, Protein Binding, Signal Transduction
Binding Sites, Glycogen Synthase Kinase 3 beta, Interleukins, Mutation, Missense, Receptors, Interleukin-1, Interleukin-33, Cell Line, Enzyme Activation, Glycogen Synthase Kinase 3, Mice, Amino Acid Substitution, Focal Adhesion Kinase 1, Animals, Protein Binding, Signal Transduction
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