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 ...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-3βand stabilized GSK-3βfrom ubiquitination and degradation.Elevated GSK-3βexpression phosphorylated A20 to inhibit its ubiquitin-editing activity,causing the accumulation of C/EBPβand 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/EBPβin AMs,which represents a target that may provide a promising treatment strategy for PF.展开更多
基金supported by grants from the National Key R&D Program of China(2017YFA0205400)the National Natural Science Foundation of China(81530093,81773781,81803604,81874316,81622010,and 81770800)+2 种基金Chinese Academy of Medical Sciences Central Public-interest Scientific Institution Basal Research Fund(2018PT35004,Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis,CAMS Key Lab,China)Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China)CAMS Innovation Fund for Medical Sciences(2016-I2M-3-008,China)。
文摘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-3βand stabilized GSK-3βfrom ubiquitination and degradation.Elevated GSK-3βexpression phosphorylated A20 to inhibit its ubiquitin-editing activity,causing the accumulation of C/EBPβand 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/EBPβin AMs,which represents a target that may provide a promising treatment strategy for PF.
