RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF.
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the most frequent of which is F508del-CFTR. CF is characterized by excessive secretion of pro-inflammatory mediators into the airway lumen, inducing a highly inflammatory cellular phenotype. This process triggers fibrosis, causing airway destruction and leading to high morbidity and mortality. We previously reported that miR-155 is upregulated in CF lung epithelial cells, but the molecular mechanisms by which miR-155 affects the disease phenotype is not understood. Here we report that RPTOR (regulatory associated protein of mTOR, complex 1) is a novel target of miR-155 in CF lung epithelial cells. The suppression of RPTOR expression and subsequent activation of TGF-β signaling resulted in the induction of fibrosis by elevating connective tissue growth factor (CTGF) abundance in CF lung epithelial cells. Thus, we propose that miR-155 might regulate fibrosis of CF lungs through the increased CTGF expression, highlighting its potential value in CF therapy.
a Molecular and Cell Biology Program, Uniformed Services University of the Health Sciences , Bethesda , MD , USA.|b Department of Anatomy , Physiology and Genetics, Uniformed Services University of the Health Sciences , Bethesda , MD , USA.
Motohiro
M
Tsuchiya
b Department of Anatomy , Physiology and Genetics, Uniformed Services University of the Health Sciences , Bethesda , MD , USA.
Swathi
S
Kalurupalle
b Department of Anatomy , Physiology and Genetics, Uniformed Services University of the Health Sciences , Bethesda , MD , USA.
Parameet
P
Kumar
b Department of Anatomy , Physiology and Genetics, Uniformed Services University of the Health Sciences , Bethesda , MD , USA.
Sarani
S
Ghoshal
c Laboratory of Genetics, National Institute on Aging, National Institutes of Health , Baltimore , MD , USA.
Yongqing
Y
Zhang
c Laboratory of Genetics, National Institute on Aging, National Institutes of Health , Baltimore , MD , USA.
Elin
E
Lehrmann
c Laboratory of Genetics, National Institute on Aging, National Institutes of Health , Baltimore , MD , USA.
Kevin G
KG
Becker
c Laboratory of Genetics, National Institute on Aging, National Institutes of Health , Baltimore , MD , USA.
Myriam
M
Gorospe
b Department of Anatomy , Physiology and Genetics, Uniformed Services University of the Health Sciences , Bethesda , MD , USA.
Roopa
R
Biswas
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000235:genetics*; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D000076223:Regulatory-Associated Protein of mTOR; D015203:Reproducibility of Results; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D055513:Connective Tissue Growth Factor
CTGF; Cystic fibrosis; RPTOR; TGF-β signaling; inflammation; lung epithelium; miR-155; microRNA