Liu S, Lv X, Wei X, Liu C, Li Q, Min J, Hua F, Zhang X, Li K, Li P, Xiao Y, Hu Z, Cui B

Pulmonary fibrosis (PF) is a chronic, progressive, fatal interstitial lung disease with limited available therapeutic strategies. We recently reported that the protein kinase glycogen synthase kinase-3? (GSK-3?) interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta (C/EBP?) in alveolar macrophages ...

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(AMs), resulting in a profibrotic phenotype of AMs and promoting the development of PF. Here, we showed that chronic lung injury upregulated the stress response protein tribbles homolog 3 (TRIB3), which interacted with GSK-3? and stabilized GSK-3? from ubiquitination and degradation. Elevated GSK-3? expression phosphorylated A20 to inhibit its ubiquitin-editing activity, causing the accumulation of C/EBP? and the production of several profibrotic factors in AMs and promoting PF development. Activated C/EBP?, in turn, increased the transcription of TRIB3 and GSK-3?, thereby establishing a positive feedback loop in AMs. The knockdown of TRIB3 expression or the pharmacologic disruption of the TRIB3?GSK-3? interaction was an effective PF treatment. Our study reveals an intact profibrotic axis of TRIB3?GSK-3??A20?C/EBP? in AMs, which represents a target that may provide a promising treatment strategy for PF.

Date: Oct. 01, 2021

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