Targeting Degradation of the Transcription Factor C/EBP? Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages.

Although recent progress provides mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), rare anti-PF therapeutics show definitive promise for treating this disease. Repeated lung epithelial injury results in injury-repairing response and inflammation, which drive the development of PF. Here, we report that chronic lung injury inactivated the ubiquitin-editing enzyme ...
A20, causing progressive accumulation of the transcription factor C/EBP? in alveolar macrophages (AMs) from PF patients and mice, which upregulated a number of immunosuppressive and profibrotic factors promoting PF development. In response to chronic lung injury, elevated glycogen synthase kinase-3? (GSK-3?) interacted with and phosphorylated A20 to suppress C/EBP? degradation. Ectopic expression of A20 or pharmacological restoration of A20 activity by disturbing the A20-GSK-3? interaction accelerated C/EBP? degradation and showed potent therapeutic efficacy against experimental PF. Our study indicates that a regulatory mechanism of the GSK-3?-A20-C/EBP? axis in AMs may be a potential target for treating PF and fibroproliferative lung diseases.
Mesh Terms:
Animals, CCAAT-Enhancer-Binding Protein-beta, Cell Line, Glycogen Synthase Kinase 3 beta, HEK293 Cells, Humans, Inflammation, Macrophages, Mice, Mice, Inbred C57BL, Phosphorylation, Pulmonary Fibrosis, Signal Transduction, Transcription Factors, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, Up-Regulation
Immunity
Date: Dec. 17, 2018
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