The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health

Abstract

SLC7A5, known as LAT1, belongs to the APC superfamily and forms a heterodimeric amino acid transporter interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide. The complex is responsible for uptake of essential amino acids in crucial body districts such as placenta and blood brain barrier. LAT1/CD98 heterodimer has been studied over the years to unravel the transport mechanism and the role of each subunit. Studies conducted in intact cells demonstrated that LAT1/CD98 mediates a Na+ and pH independent antiport of amino acids. Some novel insights into the function of LAT1 derived from studies conducted in proteoliposomes reconstituted with the recombinant human LAT1. Using this experimental tool, it has been demonstrated that the preferred substrate is histidine and that CD98 is not required for transport being, plausibly, involved in routing LAT1 to the plasma membrane. Since a 3D structure of LAT1 is not available, homology models have been built on the basis of the AdiC transporter from E.coli. Crucial residues for substrate recognition and gating have been identified using a combined approach of bioinformatics and site-directed mutagenesis coupled to functional assays. Over the years, the interest around LAT1 increased because this transporter is involved in important human diseases such as neurological disorders and cancer. Therefore, LAT1 became an important pharmacological target together with other nutrient membrane transporters. Moving from knowledge on structure/function relationships, two cysteine residues, lying on the substrate binding site, have been exploited for designing thiol reacting covalent inhibitors. Some lead compounds have been characterized whose efficacy has been tested in a cancer cell line.

Identification of genes with enriched expression in early developing mouse cone photoreceptors

“…One distinct cluster upregulates the SLC7A3 and SLC7A5 genes. SLC7A5 is a known thyroid hormone transporter for its T3/T4 states (Scalise et al, 2018) that has been reported in human fetal retinas and organoids (Eldred et al, 2018;Hoshino et al, 2017).…”

The RNA-Binding Protein YBX3 Controls Amino Acid Levels by Regulating SLC mRNA Abundance

“…YBX3 translation is reduced upon inhibition of mTORC1 by the specific inhibitor Torin-1 (Thoreen et al, 2012), suggesting that YBX3 expression is potentially regulated by cellular amino acids by mTORC1 activity, which, in turn, regulates SLC transporter expression and the import of essential amino acids. There are numerous examples of physiological and pathological conditions that require increases in SLC expression, including T cell activation, cell growth, and development, as well as cancer and inflammatory diseases (Fotiadis et al, 2013;Ren et al, 2017;Scalise et al, 2018). For example, SLC7A5 and SLC3A2 expression rapidly increase in human skeletal muscle after essential amino acid ingestion, which was suggested to be an adaptive response needed to increase amino acid uptake after eating (Drummond et al, 2010).…”

Human Intestinal Enteroids as a Model System of Shigella Pathogenesis

“…Importantly, mTOR-associated xenophagy is limited by the uptake of essential amino acids such as leucine (62); because amino acid transportation is limited by glutamine, and glutamine metabolism is altered in metastatic cell lines such as HeLa, Shigella studies of amino acid starvation and xenophagy are constrained by physiologically relevant model systems. In generalized amino acid starvation studies, autophagy is governed by the ATF4-mediated regulation of SLC7A5, a heterodimeric antiporter which couples the influx of leucine/isoleucine with the efflux of glutamine (63,64). Because S. flexneri infection depletes host leucine and isoleucine and activates ATF3, likely through the ATF4 stress response (60), we hypothesized that SLC7A5 is upregulated during S. flexneri infection of colonoid monolayers.…”