1. TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target
- Author
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Shanshan Liu, Xiaoxi Lv, Xupeng Wei, Chang Liu, Qiao Li, Jiali Min, Fang Hua, Xiaowei Zhang, Ke Li, Pingping Li, Yang Xiao, Zhuowei Hu, and Bing Cui
- Subjects
E3 ligase ,Lung injury ,Protein phosphorylation ,Protein–protein interaction ,Ubiquitination ,TRIB3 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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-3β (GSK-3β) interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) in alveolar macrophages (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-3β and stabilized GSK-3β from ubiquitination and degradation. Elevated GSK-3β expression phosphorylated A20 to inhibit its ubiquitin-editing activity, causing the accumulation of C/EBPβ and the production of several profibrotic factors in AMs and promoting PF development. Activated C/EBPβ, in turn, increased the transcription of TRIB3 and GSK-3β, thereby establishing a positive feedback loop in AMs. The knockdown of TRIB3 expression or the pharmacologic disruption of the TRIB3‒GSK-3β interaction was an effective PF treatment. Our study reveals an intact profibrotic axis of TRIB3‒GSK-3β‒A20‒C/EBPβ in AMs, which represents a target that may provide a promising treatment strategy for PF.
- Published
- 2021
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