Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids

Abstract

Reabsorption of amino acids (AAs) across the renal proximal tubule is crucial for intracellular and whole organism AA homeostasis. Although the luminal transport step is well understood, with several diseases caused by dysregulation of this process, the basolateral transport step is not understood. In humans, only cationic aminoaciduria due to malfunction of the basolateral transporter yLAT1/CD98hc (SLC7A7/SLC3A2), which mediates the export of cationic AAs, has been described. Thus, the physiologic roles of basolateral transporters of neutral AAs, such as the antiporter LAT2/CD98hc (SLC7A8/SLC3A2), a heterodimer that exports most neutral AAs, and the uniporter TAT1 (SLC16A10), which exports only aromatic AAs, remain unclear. Functional cooperation between TAT1 and LAT2/CD98hc has been suggested by studies but has not been evaluated To study the functional relationship of TAT1 and LAT2/CD98hc , we generated a double-knockout mouse model lacking TAT1 and LAT2, the catalytic subunit of LAT2/CD98hc (dKO LAT2-TAT1 mice). Compared with mice lacking only TAT1 or LAT2, dKO LAT2-TAT1 mice lost larger amounts of aromatic and other neutral AAs in their urine due to a tubular reabsorption defect. Notably, dKO mice also displayed decreased tubular reabsorption of cationic AAs and increased expression of yLAT1/CD98hc. The LAT2/CD98hc and TAT1 transporters functionally cooperate , and yLAT1/CD98hc may compensate for the loss of LAT2/CD98hc and TAT1, functioning as a neutral AA exporter at the expense of some urinary loss of cationic AAs. Cooperative and compensatory mechanisms of AA transporters may explain the lack of basolateral neutral aminoacidurias in humans.

Choroid plexus LAT2 and SNAT3 as partners in CSF amino acid homeostasis maintenance

“…We confirmed ablation of LAT2 transporter in CP on mRNA and protein levels (Additional file 1: Figure S2A, B) and measured amino acid levels in plasma and CSF samples. Previously Braun et al had reported elevated levels of 8 amino acids (Ala, Ser, Gly, Thr, Glu, Asp and Lys) for the serum of LAT2 knockout (KO) animals [37], however these alterations were not reproduced in our experiments using another LAT2 knock-out model (Additional file 2: Table S3) [32,33]. Therefore, we compared the CSF/ plasma ratio of each out of 19 detected amino acids [18 proteinogenic AA (all except Cys and Ile) and Tau] between wild type and LAT2 KO animals.…”

“…Based on their mRNA expression level, their known transport function and our published experience with kidney proximal tubule epithelial amino acid transport, we postulate, that the antiporter y + LAT2 (Slc7a6) and the lower expressed (at mRNA level) antiporter y + LAT1 (Slc7a7) and the uniporters LAT4 (SLC43a2) and TAT1 (Slc16a10) play important roles ( Fig. 4) [32]. A limitation of our study and of our speculative transport schema shown in Fig.…”

“…2d, m) and anti-SNAT1 (Fig. 2g, p) antibodies [30][31][32][33][34]. The fact that we localized only these three amino acid transporters may be considered as a limitation in view of the larger number of transporters detected at the mRNA level, but since protein localization studies are per se prone to artefacts (cross-reactivity etc.…”

Anticipation of food intake induces phosphorylation switch to regulate basolateral amino acid transporter LAT4 (SLC43A2) function

“…Thereby, uniporters are also necessary for the net efflux of non-essential neutral and cationic amino acids (Rossier et al 1999;Meier et al 2002;Dave et al 2004;Bodoy et al 2005;Ramadan et al 2007;Guetg et al 2015; for reviews see Verrey, 2003;Poncet & Taylor, 2013;Broer & Broer, 2017). It has also been suggested that basolateral uniporters might quantitatively control overall basolateral amino acid efflux (Mariotta et al 2012;Guetg et al 2015;Vilches et al 2018).…”

Amino Acid Transport Defects in Human Inherited Metabolic Disorders

“…Recently, a homozygous mutation in SLC7A8 has been identified in a family with congenital cataracts [212]. The amino acid transporter TAT1 may have a modifying influence on the development of cataracts [212,213].…”