Cereblon contributes to the development of pulmonary fibrosis via inactivation of adenosine monophosphate-activated protein kinase α1

• Published in: Experimental & molecular medicine 2021, 53(0), , pp.1-9
• Main Authors: Kang, Hyo Jae, Lee, Kyung Jin, Woo, Jisu, Kim, Jiyeon, Kim, Yun Kyu, Lee, Chang-Hoon, Yoo, Chul-Gyu, Lee, Kyoung-Hee
• Format: Article
• Language: English
• Subjects: 42/109; 631/45; 64/60; 692/420; 82/29; 82/80; 96/95; Actin; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenosine; Adenosine kinase; AMP; AMP-Activated Protein Kinases - antagonists & inhibitors; Animals; Biomarkers; Biomedical and Life Sciences; Biomedicine; Bleomycin; Bronchus; Cell Differentiation; Cells, Cultured; Collagen; Disease Models, Animal; Female; Fibroblasts; Fibroblasts - metabolism; Fibronectin; Fibrosis; Gene expression; Humans; Kinases; Lung diseases; Lungs; Medical Biochemistry; Metabolic pathways; Metformin; Mice; Mice, Knockout; Models, Biological; Molecular Medicine; Myofibroblasts - metabolism; Protein kinase; Proteins; Pulmonary fibrosis; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - metabolism; Respiratory function; Smad Proteins - metabolism; Smad3 protein; Smooth muscle; Stem Cells; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta2 - metabolism; Transforming growth factor-b1; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00619-6

Pulmonary fibrosis is a progressive and lethal lung disease characterized by the proliferation and differentiation of lung fibroblasts and the accumulation of extracellular matrices. Since pulmonary fibrosis was reported to be associated with adenosine monophosphate-activated protein kinase (AMPK) activation, which is negatively regulated by cereblon (CRBN), we aimed to determine whether CRBN is involved in the development of pulmonary fibrosis. Therefore, we evaluated the role of CRBN in bleomycin (BLM)-induced pulmonary fibrosis in mice and in transforming growth factor-beta 1 (TGF-β1)-induced differentiation of human lung fibroblasts. BLM-induced fibrosis and the mRNA expression of collagen and fibronectin were increased in the lung tissues of wild-type (WT) mice; however, they were significantly suppressed in Crbn knockout (KO) mice. While the concentrations of TGF-β1/2 in bronchoalveolar lavage fluid were increased via BLM treatment, they were similar between BLM-treated WT and Crbn KO mice. Knockdown of CRBN suppressed TGF-β1-induced activation of small mothers against decapentaplegic 3 (SMAD3), and overexpression of CRBN increased it. TGF-β1-induced activation of SMAD3 increased α-smooth muscle actin (α-SMA) and collagen levels. CRBN was found to be colocalized with AMPKα1 in lung fibroblasts. CRBN overexpression inactivated AMPKα1. When cells were treated with metformin (an AMPK activator), the CRBN-induced activation of SMAD3 and upregulation of α-SMA and collagen expression were significantly suppressed, suggesting that increased TGF-β1-induced activation of SMAD3 via CRBN overexpression is associated with AMPKα1 inactivation. Taken together, these data suggest that CRBN is a profibrotic regulator and maybe a potential target for treating lung fibrosis. Lung disease: Putting the brakes on fibrosis Interventions that target a regulatory protein called cereblon could help reduce the damage inflicted on the lungs by idiopathic pulmonary fibrosis (IPF). This incurable and generally fatal condition is associated with the accumulation of scar tissue in the lungs, which leads to the gradual loss of respiratory function. Researchers led by Kyoung-Hee Lee at Seoul National University Hospital in South Korea have now identified cereblon as a potentially important contributor to this scarring process. They found that cereblon regulates a complex metabolic pathway that ultimately contributes to production of fibrosis-related proteins in a mouse model of IPF.