Slc17a5, encoding the lysosomal transmembrane protein sialin, is crucial for lysosomal function. It is involved in the transport of free sialic acid out of the lysosome, and its deficiency leads to free sialic acid storage disorders (FSASDs) [1,3,4]. It also functions as an electrogenic 2NO₃⁻/H⁺ cotransporter in the plasma membrane of salivary gland acinar cells, mediating nitrate influx and contributing to nitrate recycling and nitrite-NO homeostasis [2].

Base editing of the SLC17A5 c.115C>T (p.Arg39Cys) variant in human dermal fibroblasts and mouse embryonic fibroblasts demonstrated significant free sialic acid reduction, indicating the potential of base editing as a therapy for FSASD [1]. In a mouse model of dietary nitrate regulation, Slc17a5 expression increased in colon epithelial cells with nitrate supplementation, and epithelial cell-conditional Slc17a5-knockout mutant mice showed decreased functional proteins of the colon epithelial barrier and intestinal epithelial cell proliferation, suggesting its role in maintaining colonic homeostasis [5].

In conclusion, Slc17a5 is essential for lysosomal sialic acid transport and nitrate handling in specific cell types. Mouse models, including knockout models, have been instrumental in revealing its role in FSASD and in maintaining colonic epithelial homeostasis, providing insights into potential therapeutic approaches for related diseases [1,5].

References:

1. Harb, Jerry F, Christensen, Chloe L, Kan, Shih-Hsin, Huang, Jeffrey Y, Wang, Raymond Y. 2023. Base editing corrects the common Salla disease SLC17A5 c.115C>T variant. In Molecular therapy. Nucleic acids, 34, 102022. doi:10.1016/j.omtn.2023.08.024. https://pubmed.ncbi.nlm.nih.gov/37727271/

2. Qin, Lizheng, Liu, Xibao, Sun, Qifei, Ambudkar, Indu S, Wang, Songlin. 2012. Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane. In Proceedings of the National Academy of Sciences of the United States of America, 109, 13434-9. doi:10.1073/pnas.1116633109. https://pubmed.ncbi.nlm.nih.gov/22778404/

3. Tarailo-Graovac, Maja, Drögemöller, Britt I, Wasserman, Wyeth W, van Karnebeek, Clara D M, Blomqvist, Maria. 2017. Identification of a large intronic transposal insertion in SLC17A5 causing sialic acid storage disease. In Orphanet journal of rare diseases, 12, 28. doi:10.1186/s13023-017-0584-6. https://pubmed.ncbi.nlm.nih.gov/28187749/

4. Aula, N, Salomäki, P, Timonen, R, Aula, P, Peltonen, L. 2000. The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. In American journal of human genetics, 67, 832-40. doi:. https://pubmed.ncbi.nlm.nih.gov/10947946/

5. Wang, Xue, Liu, Huan, Yue, Mingwei, Wang, Songlin, Hu, Lei. 2024. Dietary nitrate maintains intestinal epithelia homeostasis in aged mice. In Biogerontology, 25, 1171-1187. doi:10.1007/s10522-024-10127-5. https://pubmed.ncbi.nlm.nih.gov/39162978/