ADAR1 Isoforms Regulate Let-7d Processing in Idiopathic Pulmonary Fibrosis

Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generat...

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Published in:International journal of molecular sciences 2022-08, Vol.23 (16), p.9028
Main Authors: Díaz-Piña, Gabriela, Rubio, Karla, Ordoñez-Razo, Rosa M., Barreto, Guillermo, Montes, Eduardo, Becerril, Carina, Salgado, Alfonso, Cabrera-Fuentes, Héctor, Aquino-Galvez, Arnoldo, Carlos-Reyes, Angeles, Ruiz, Victor
Format: Article
Language:English
Subjects:
ADAR
Adenosine
Adenosine deaminase
Double-stranded RNA
Editing
Fibroblasts
Fibrosis
IPF
Isoforms
Life Sciences
Lung diseases
Maturation
MicroRNAs
miRNA
Plasmids
Proteins
Pulmonary fibrosis
RNA edition
Smad2 protein
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Summary:Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by an alternative promoter. Let-7d is considered an essential microRNA in Pulmonary Fibrosis (PF). In silico analysis revealed COL3A1 and SMAD2, proteins involved in the development of IPF, as Let-7d targets. We analyzed the role of ADAR1-p110 and ADAR1-p150 isoforms in the regulation of Let-7d maturation and the effect of this regulation on the expression of COL3A1 and SMAD2 in IPF fibroblast. We demonstrated that differential expression and subcellular distribution of ADAR1 isoforms in fibroblasts contribute to the up-regulation of pri-miR-Let-7d and down-regulation of mature Let-7d. Induction of overexpression of ADAR1 reestablishes the expression of pri-miR-Let-7d and Let-7d in lung fibroblasts. The reduction of mature Let-7d upregulates the expression of COL3A1 and SMAD2. Thus, ADAR1 isoforms and Let-7d could have a synergistic role in IPF, which is a promising explanation in the mechanisms of fibrosis development, and the regulation of both molecules could be used as a therapeutic approach in IPF.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23169028