title: Interleukin 17A inhibits autophagy through activation of PIK3CA to interrupt the GSK3B-mediated degradation of BCL2 in lung epithelial cells.
abstract: We recently found that activation of IL17A signaling promotes the development and progression of acute and chronic pulmonary fibrosis, and that the blockade of IL17A activity attenuates pulmonary fibrosis by promoting the resolution of inflammation and the activation of autophagy. Although the induction of autophagy stimulating the collagen degradation in the fibrotic lung tissue has been identified as a mechanism responsible for the antifibrotic role of targeting IL17A, it remains to be clarified how IL17A signaling suppresses autophagy. Here we report that the phosphorylation of B-cell CLL/lymphoma 2 (BCL2), an apoptosis regulatory protein, was inhibited in the presence of IL17A in lung epithelial cells, and this reduction suppressed the ubiquitination degradation of BCL2, which subsequently attenuated autophagy by promoting the interaction of BCL2 and BECN1. We found that IL17A regulated the phosphorylation of BCL2 through activating the phosphoinositide 3-kinase (PI3K)-glycogen synthase kinase 3 β (GSK3B) signaling cascade. In response to IL17A stimulation, PI3K was activated and resulted in phosphorylation of GSK3B at Ser9, which subsequently attenuated the interaction of GSK3B with BCL2. Interrupting the GSK3B and BCL2 interaction precluded the phosphorylation of BCL2 at Ser70, which could trigger the ubiquitination degradation, and restrained the ubiquitination degradation of BCL2. Consequently, a decrease in the BCL2 degradation induced by IL17A resulted in a suppressed autophagy in lung epithelial cells. These findings indicate that the IL17A-PI3K-GSK3B-BCL2 signaling pathway participates in the attenuation of autophagic activity in lung epithelial cells, which is attributed to be primarily responsible for the development and progression of IL17A-induced pulmonary fibrosis.
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Su
authors.initials: S
authors.lastname: Mi
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Zhuo-Wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001761:Bleomycin; D058534:Class I Phosphatidylinositol 3-Kinases; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D008168:Lung / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000473:pathology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D001761:Bleomycin; D058534:Class I Phosphatidylinositol 3-Kinases; D003513:Cycloheximide; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D020381:Interleukin-17; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D010768:Phosphoserine; D019253:Proto-Oncogene Proteins c-bcl-2; C491997:BECN1 protein, human; C546639:Pik3ca protein, mouse; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse
keywords: IL17A signaling pathway; inflammatory disease; protein interaction; protein stability; pulmonary fibrosis; ubiquitination degradation