AUTHOR=Mercier Julia , Calmel Claire , Mésinèle Julie , Sutanto Erika , Merabtene Fatiha , Longchampt Elisabeth , Sage Edouard , Kicic Anthony , Boëlle Pierre-Yves , Corvol Harriet , Ruffin Manon , Guillot Loïc 

TITLE=SLC6A14 Impacts Cystic Fibrosis Lung Disease Severity via mTOR and Epithelial Repair Modulation

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.850261

DOI=10.3389/fmolb.2022.850261

ISSN=2296-889X

ABSTRACT=<p>Cystic fibrosis (CF), due to pathogenic variants in <italic>CFTR</italic> gene, is associated with chronic infection/inflammation responsible for airway epithelium alteration and lung function decline. Modifier genes induce phenotype variability between people with CF (pwCF) carrying the same <italic>CFTR</italic> variants. Among these, the gene encoding for the amino acid transporter SLC6A14 has been associated with lung disease severity and age of primary airway infection by the bacteria <italic>Pseudomonas aeruginosa</italic>. In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within <italic>SLC6A14</italic> promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on <italic>SLC6A14</italic> promoter activity using a luciferase reporter and the role of SLC6A14 in the mechanistic target of rapamycin kinase (mTOR) signaling pathway and airway epithelial repair. We confirm that <italic>SLC6A14</italic> rs3788766 SNP is associated with lung disease severity in pwCF (<italic>p</italic> = 0.020; <italic>n</italic> = 3,257, pancreatic insufficient, aged 6–40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for <italic>CFTR</italic>, <italic>SLC6A14</italic> promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced <sup>3</sup>H-arginine transport, mTOR phosphorylation, and bronchial epithelial repair rates in wound healing assays. To conclude, our study highlights that <italic>SLC6A14</italic> genotype might affect lung disease severity of people with cystic fibrosis <italic>via</italic> mTOR and epithelial repair mechanism modulation in the lung.</p>