TRIB3-GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target

• 作者: Shanshan Liu Xiaoxi Lv Xupeng Wei Chang Liu Qiao Li Jiali Min Fang Hua Xiaowei Zhang Ke Li Pingping Li Yang Xiao Zhuowei Hu Bing Cui
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（10）
• 所属期刊栏目: Original articles
• 页码范围: 3105-3119
• 页数: 15页
• 语种: 英文

摘要

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-3βinteraction 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.