SLC6A14, an amino acid transporter, modifies the primary CF defect in fluid secretion

ELife
Saumel AhmadiChristine E Bear

Abstract

The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identified SLC6A14, an electrogenic amino acid transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current work was to determine the biological role of Slc6a14, by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the intestinal fluid secretion defect, characteristic of these mice. In vitro studies of mouse intestinal organoids revealed that exacerbation of the primary defect was associated with reduced arginine uptake across the apical membrane, with aberrant nitric oxide and cyclic GMP-mediated regulation of the major CF-causing mutant protein. Together, these studies highlight the role of this apical transporter in modifying cellular nitric oxide levels, residual function of the major CF mutant and potentially, its promise as a therapeutic target.

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Citations

Mar 14, 2020·Cellular and Molecular Life Sciences : CMLS·Manon RuffinLoic Guillot
Dec 12, 2020·Journal of Clinical Medicine·Sofna BanjarnahorRenke Maas
Nov 17, 2020·Frontiers in Cell and Developmental Biology·Katarzyna A Nałęcz
May 1, 2021·Frontiers in Molecular Biosciences·Stephen J FairweatherStefan Bröer
May 23, 2021·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Vinciane Saint-CriqMichael A Gray

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Methods Mentioned

BETA
confocal microscopy
Fluorescence imaging
PCR
co-immunoprecipitation
co-IP
genotyping
Profiler
ELISA
enzyme-linked immunosorbent assay
protein assay

Software Mentioned

3DHISTECH
Volocity
Cell Profiler
NetPhosK
CellProfiler
GraphPad Prism
ImageJ

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