Slc6a14, also known as amino acid transporter B0,+ (ATB0,+), is a Na+/Cl--coupled transporter that imports and concentrates all neutral amino acids, as well as lysine and arginine, into the cytoplasm of different cell types [3,4,5]. It is involved in the glutaminolysis and serine-glycine-one-carbon pathways, which are reprogramed and upregulated in cancer to support cell growth and proliferation [3]. Additionally, it may play a role in maintaining epithelial integrity and anti-infective response in the airways [2].

In ulcerative colitis (UC), Slc6a14 knockdown markedly suppressed ferroptosis, and it was found to facilitate ferroptosis by promoting C/EBPβ expression and binding activity to inhibit PAK6 expression [1]. In cystic fibrosis, Slc6a14 is a modifier gene that may modulate the anti-infective response and epithelial integrity of the airways, and its SNP rs3788766 is associated with lung disease severity, with the minor allele G being deleterious [2,7]. In breast cancer, its expression is upregulated in estrogen receptor positive cells, and inhibition of heat shock protein 90β, which interacts with Slc6a14, decreases its transport activity and cell-surface level [4,8]. Also, Slc6a14 -/- mice on a high-fat diet gained more weight, developed fatty liver and metabolic syndrome, indicating a link between Slc6a14 deficiency and obesity under such dietary conditions [6].

In conclusion, Slc6a14 plays a crucial role in multiple biological processes, especially in cancer-related metabolism, and in the pathophysiology of ulcerative colitis, cystic fibrosis, and obesity-related metabolic disorders. Gene knockout mouse models, like the Slc6a14 -/- mice, have been instrumental in revealing its functions in these disease conditions, helping us understand its underlying mechanisms and potential as a therapeutic target.

References:

1. Chen, Yanjun, Yan, Wenying, Chen, Yuqi, Shi, Tongguo, Chen, Weichang. 2022. SLC6A14 facilitates epithelial cell ferroptosis via the C/EBPβ-PAK6 axis in ulcerative colitis. In Cellular and molecular life sciences : CMLS, 79, 563. doi:10.1007/s00018-022-04594-7. https://pubmed.ncbi.nlm.nih.gov/36272033/

2. Ruffin, M, Mercier, J, Calmel, C, Corvol, H, Guillot, L. 2020. [SLC6A14, a modifier gene in cystic fibrosis]. In Revue des maladies respiratoires, 37, 218-221. doi:10.1016/j.rmr.2020.02.008. https://pubmed.ncbi.nlm.nih.gov/32146055/

3. Sniegowski, Tyler, Korac, Ksenija, Bhutia, Yangzom D, Ganapathy, Vadivel. 2021. SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine-Glycine-One-Carbon Pathways in Cancer. In Pharmaceuticals (Basel, Switzerland), 14, . doi:10.3390/ph14030216. https://pubmed.ncbi.nlm.nih.gov/33806675/

4. Nałęcz, Katarzyna A. 2020. Amino Acid Transporter SLC6A14 (ATB0,+) - A Target in Combined Anti-cancer Therapy. In Frontiers in cell and developmental biology, 8, 594464. doi:10.3389/fcell.2020.594464. https://pubmed.ncbi.nlm.nih.gov/33195271/

5. Ruffin, Manon, Mercier, Julia, Calmel, Claire, Corvol, Harriet, Guillot, Loic. 2020. Update on SLC6A14 in lung and gastrointestinal physiology and physiopathology: focus on cystic fibrosis. In Cellular and molecular life sciences : CMLS, 77, 3311-3323. doi:10.1007/s00018-020-03487-x. https://pubmed.ncbi.nlm.nih.gov/32166393/

6. Sivaprakasam, Sathish, Sikder, Mohd O F, Ramalingam, Latha, Wachtel, Mitchell S, Ganapathy, Vadivel. 2021. SLC6A14 deficiency is linked to obesity, fatty liver, and metabolic syndrome but only under conditions of a high-fat diet. In Biochimica et biophysica acta. Molecular basis of disease, 1867, 166087. doi:10.1016/j.bbadis.2021.166087. https://pubmed.ncbi.nlm.nih.gov/33513428/

7. Mercier, Julia, Calmel, Claire, Mésinèle, Julie, Ruffin, Manon, Guillot, Loïc. 2022. SLC6A14 Impacts Cystic Fibrosis Lung Disease Severity via mTOR and Epithelial Repair Modulation. In Frontiers in molecular biosciences, 9, 850261. doi:10.3389/fmolb.2022.850261. https://pubmed.ncbi.nlm.nih.gov/35372502/

8. Połosak, Karolina, Papierniak-Wyglądała, Anna, Nałęcz, Katarzyna A. 2022. Regulation of SLC6A14 trafficking in breast cancer cells by heat shock protein HSP90β. In Biochemical and biophysical research communications, 614, 41-46. doi:10.1016/j.bbrc.2022.05.011. https://pubmed.ncbi.nlm.nih.gov/35569376/