circELP2 reverse-splicing biogenesis and function as a pro-fibrogenic factor by targeting mitochondrial quality control pathway.
Songzi ZhangDiwei TuWeili LiuRuiqiong LiMengqi JiangXinglong YuanJianlin LuanHongbo LiChangjun LvXiaodong SongPublished in: Journal of cellular and molecular medicine (2023)
Idiopathic pulmonary fibrosis (IPF) is considered as a chronic, fibrosing interstitial pneumonia with unknown mechanism. The present work aimed to explore the function, biogenesis and regulatory mechanism of circELP2 in pulmonary fibrosis and evaluate the value of blocking circELP2-medicated signal pathway for IPF treatment. The results showed that heterogeneous nuclear ribonucleoprotein L initiated reverse splicing of circELP2 resulting in the increase of circELP2 generation. The biogenetic circELP2 activated the abnormal proliferation and migration of fibroblast and extracellular matrix deposition to promote pulmonary fibrogenesis. Mechanistic studies demonstrated that cytoplasmic circELP2 sponged miR-630 to increase transcriptional co-activators Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ). Then, YAP1/TAZ bound to the promoter regions of their target genes, such as mTOR, Raptor and mLST8, which in turn activated or inhibited the genes expression in mitochondrial quality control pathway. Finally, the overexpressed circELP2 and miR-630 mimic were packaged into adenovirus vector for spraying into the mice lung to evaluate therapeutic effect of blocking circELP2-miR-630-YAP1/TAZ-mitochondrial quality control pathway in vivo. In conclusion, blocking circELP2-medicated pathway can alleviate pulmonary fibrosis, and circELP2 may be a potential target to treat lung fibrosis.
Keyphrases
- quality control
- idiopathic pulmonary fibrosis
- pulmonary fibrosis
- cell proliferation
- long non coding rna
- transcription factor
- extracellular matrix
- oxidative stress
- gene expression
- interstitial lung disease
- long noncoding rna
- pulmonary hypertension
- dna methylation
- type diabetes
- immune response
- intensive care unit
- genome wide
- systemic sclerosis
- adipose tissue
- metabolic syndrome
- single molecule
- sensitive detection
- skeletal muscle
- insulin resistance
- dna binding
- respiratory failure