Alternative titles; symbols
HGNC Approved Gene Symbol: SLC43A2
Cytogenetic location: 17p13.3 Genomic coordinates (GRCh38): 17:1,569,254-1,630,088 (from NCBI)
System L amino acid transporters, such as SLC43A2, mediate sodium-independent transport of bulky neutral amino acids across cell membranes (Bodoy et al., 2005).
By searching a database for sequences similar to LAT3 (SLC43A1; 603733), Bodoy et al. (2005) identified SLC43A2, which they called LAT4. The deduced 569-amino acid protein has a calculated molecular mass of 62.7 kD. LAT4 has 12 transmembrane domains with intracellular N and C termini, and a putative N-glycosylation site is located in the extracellular loop between the first 2 transmembrane domains. It shares 57% amino acid identity with LAT3 and 91% identity with mouse Lat4. Northern blot analysis of human tissues detected transcripts of 3.1 and 8 to 9 kb, with highest expression in placenta, followed by kidney and peripheral blood leukocytes. In mouse tissues, expression was highest in small intestine. Immunofluorescence analysis detected LAT4 on the plasma membrane of transfected HeLa cells. In situ hybridization of human kidney showed LAT4 mRNA restricted to epithelial cells of the distal tubule and collecting duct. In mouse intestine, Lat4 was mainly expressed in crypt cells of the intestinal microvilli and in epithelial cells at the base of the villus. Western blot analysis of transfected HeLa cells showed that endoglycosidase treatment reduced the molecular mass of LAT4, confirming that LAT4 is glycosylated.
Bodoy et al. (2005) found that injection of human LAT4 cRNA into Xenopus oocytes resulted in increased uptake of L-phenylalanine, L-leucine, L-isoleucine, and L-methionine. L-phenylalanine transport was independent of chloride, sodium, and pH. Kinetic analysis of L-phenylalanine and L-leucine transport activity revealed a low-affinity component that was sensitive to the sulfhydryl-specific reagent N-ethylmaleimide and a high-affinity component that was not. Substitution of the conserved ser297 in the large intracellular loop of LAT4 with ala partially inhibited transport activity and abolished the sensitivity to N-ethylmaleimide. Lat4 activity localized to basolateral membranes in cultured mouse proximal collecting tubule kidney cells.
Bian et al. (2020) showed that tumor cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine-79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 (601511) and impaired T cell immunity. Mechanistically, tumor cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumor SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumor immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumor-bearing mice and patients with colon cancer. Clinically, tumor SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Bian et al. (2020) concluded that their results identified a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumor microenvironment. The authors suggested that cancer methionine consumption is an immune evasion mechanism, and that targeting cancer methionine signaling may provide an immunotherapeutic approach.
Hartz (2007) mapped the SLC43A2 gene to chromosome 17p13.3 based on an alignment of the SLC43A2 sequence (GenBank AB120364) with the genomic sequence (build 36.1).
Bian, Y., Li, W., Kremer, D. M., Sajjakulnukit, P., Li, S., Crespo, J., Nwosu, Z. C., Zhang, L., Czerwonka, A., Pawlowska, A., Xia, H., Li, J., and 14 others. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585: 277-282, 2020. [PubMed: 32879489] [Full Text: https://doi.org/10.1038/s41586-020-2682-1]
Bodoy, S., Martin, L., Zorzano, A., Palacin, M., Estevez, R., Bertran, J. Identification of LAT4, a novel amino acid transporter with system L activity. J. Biol. Chem. 280: 12002-12011, 2005. [PubMed: 15659399] [Full Text: https://doi.org/10.1074/jbc.M408638200]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/22/2007.