TY - JOUR TI - SLC6A14, an amino acid transporter, modifies the primary CF defect in fluid secretion AU - Ahmadi, Saumel AU - Xia, Sunny AU - Wu, Yu-Sheng AU - Di Paola, Michelle AU - Kissoon, Randolph AU - Luk, Catherine AU - Lin, Fan AU - Du, Kai AU - Rommens, Johanna AU - Bear, Christine E A2 - Aldrich, Richard A2 - DeBerardinis, Ralph VL - 7 PY - 2018 DA - 2018/07/13 SP - e37963 C1 - eLife 2018;7:e37963 DO - 10.7554/eLife.37963 UR - https://doi.org/10.7554/eLife.37963 AB - 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. KW - organoids KW - colonic cell line KW - nitric oxide signaling KW - amino acid transporter KW - F508del-CFTR JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -