Essential amino acid transporter Lat4 (<i>Slc43a2</i>) is required for mouse development

Guetg, Adriano; Mariotta, Luca; Bock, Lukas; Herzog, Brigitte; Fingerhut, Ralph; Camargo, Simone M. R.; Verrey, François

doi:10.1113/jphysiol.2014.283960

Cited by 56 publications

(70 citation statements)

References 51 publications

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“…Altogether, these data strongly suggest that LAT3 and LAT4 directly contribute to the efflux of 3,3Ј-T2 and MIT. The physiological role of iodothyronine export by LAT3 and LAT4 in vivo remains to be elucidated, for example by measuring TH levels in the Lat3 KO zebrafish model and the lat4 knockout mice (51,52). Uptake of the different substrates by LAT1 and LAT2 is dependent on the pH in the incubation medium as we found a significant increase in uptake by decreasing the pH from 7.3 to 6.3 or 5.3 ( Figure 8).…”

Section: Discussionmentioning

confidence: 71%

“…A zebrafish morphant lacking Lat3 function showed collapsed glomeruli and disruption of glomerular permeability, suggesting that LAT3 may play a crucial role in the development and maintenance of podocyte structure and function (51). Recently, the group of Verrey et al showed that LAT4 facilitates the uptake and efflux amino acids and that LAT4 is important in nutrition during early development (52). In Lat4 KO mice, they observed intrauterine and postnatal growth retardation, low amniotic amino acid concentrations and premature death after 9 days.…”

Section: Discussionmentioning

confidence: 97%

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Transport of Iodothyronines by Human L-Type Amino Acid Transporters

et al. 2015

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Thyroid hormone (TH) transporters facilitate cellular TH influx and efflux, which is paramount for normal physiology. The L-type amino acid transporters LAT1 and LAT2 are known to facilitate TH transport. However, the role of LAT3, LAT4, and LAT5 is still unclear. Therefore, the aim of this study was to further characterize TH transport by LAT1 and LAT2 and to explore possible TH transport by LAT3, LAT4, and LAT5. FLAG-LAT1-5 constructs were transiently expressed in COS1 cells. LAT1 and LAT2 were cotransfected with the CD98 heavy chain. Cellular transport was measured using 10 nM (125)I-labeled T4, T3, rT3, 3,3'-T2, and 10 μM [(125)I]3'-iodotyrosine (MIT) as substrates. Intracellular metabolism of these substrates was determined in cells cotransfected with either of the LATs with type 1 or type 3 deiodinase. LAT1 facilitated cellular uptake of all substrates and LAT2 showed a net uptake of T3, 3,3'-T2, and MIT. Expression of LAT3 or LAT4 did not affect transport of T4 and T3 but resulted in the decreased cellular accumulation of 3,3'-T2 and MIT. LAT5 did not facilitate the transport of any substrate. Cotransfection with LAT3 or LAT4 strongly diminished the cellular accumulation of 3,3'-T2 and MIT by LAT1 and LAT2. These data were confirmed by metabolism studies. LAT1 and LAT2 show distinct preferences for the uptake of the different iodocompounds, whereas LAT3 and LAT4 specifically facilitate the 3,3'-T2 and MIT efflux. Together our findings suggest that different sets of transporters with specific influx or efflux capacities may cooperate to regulate the cellular thyroid state.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 97%

Transport of Iodothyronines by Human L-Type Amino Acid Transporters

et al. 2015

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“…; Guetg et al . ; for reviews see Verrey, ; Poncet & Taylor, ; Broer & Broer, ). It has also been suggested that basolateral uniporters might quantitatively control overall basolateral amino acid efflux (Mariotta et al .…”

Section: Introductionmentioning

confidence: 99%

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

Oparija

Rajendran

Poncet

et al. 2018

The Journal of Physiology

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Key points Amino acid absorption requires luminal uptake into and subsequent basolateral efflux out of epithelial cells, with the latter step being critical to regulate the intracellular concentration of the amino acids. The basolateral essential neutral amino acid uniporter LAT4 (SLC43A2) has been suggested to drive the net efflux of non‐essential and cationic amino acids via parallel amino acid antiporters by recycling some of their substrates; its deletion has been shown to cause defective postnatal growth and death in mice. Here we test the regulatory function of LAT4 phosphorylation sites by mimicking their phosphorylated and dephosphorylated states in Xenopus laevis oocytes and show that dephosphorylation of S274 and phosphorylation of S297 increase LAT4 membrane localization and function. Using new phosphorylation site‐specific antibodies, we observe changes in LAT4 phosphorylation in mouse small intestine that correspond to its upregulation at the expected feeding time. These results strongly suggest that LAT4 phosphorylation participates in the regulation of transepithelial amino acid absorption. Abstract The essential amino acid uniporters LAT4 and TAT1 are located at the basolateral side of intestinal and kidney epithelial cells and their transport function has been suggested to control the transepithelial (re)absorption of neutral and possibly also cationic amino acids. Uniporter LAT4 selectively transports the branched chain amino acids leucine, isoleucine and valine, and additionally methionine and phenylalanine. Its deletion leads to a postnatal growth failure and early death in mice. Since LAT4 has been reported to be phosphorylated in vivo, we hypothesized that phosphorylation regulates its function. Using Xenopus laevis oocytes, we tested the impact of LAT4 phosphorylation at Ser274 and Ser297 by expressing mutant constructs mimicking phosphorylated and dephosphorylated states. We then investigated the in vivo regulation of LAT4 in mouse small intestine using new phosphorylation site‐specific antibodies and a time‐restricted diet. In Xenopus oocytes, mimicking non‐phosphorylation of Ser274 led to an increase in affinity and apparent surface membrane localization of LAT4, stimulating its transport activity, while the same mutation of Ser297 decreased LAT4's apparent surface expression and transport rate. In wild‐type mice, LAT4 phosphorylation on Ser274 was uniform at the beginning of the inactive phase (ZT0). In contrast, at the beginning of the active phase (ZT12), corresponding to the anticipated feeding time, Ser274 phosphorylation was decreased and restricted to relatively large patches of cells, while Ser297 phosphorylation was increased. We conclude that phosphorylation of small intestinal LAT4 is under food‐entrained circadian control, leading presumably to an upregulation of LAT4 function at the anticipated feeding time.

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“…Remaining follicular layers were removed manually and non-injected (NI) oocytes were either tested naïve or injected with 10 ng of hLAT4 or 25 ng of hATB 0,+ cRNA. Oocytes were incubated for three days at 16 °C in modified Barth’s solution (88 mM NaCl, 1 mM KCl, 0.82 mM MgSO 4 , 0.41 mM CaCl 2 , 0.33 mM Ca(NO 3 ) 2 , 2.4 mM NaHCO 3 , 10 mM HEPES, 5 mg/l Gentamicin, 5 mg/l Doxycycline) before assaying22.…”

Section: Methodsmentioning

confidence: 99%

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

Taslimifar

Oparija

Verrey

et al. 2017

Sci Rep

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Determining the contributions of different transporter species to overall cellular transport is fundamental for understanding the physiological regulation of solutes. We calculated the relative activities of Solute Carrier (SLC) transporters using the Michaelis-Menten equation and global fitting to estimate the normalized maximum transport rate for each transporter (Vmax). Data input were the normalized measured uptake of the essential neutral amino acid (AA) L-leucine (Leu) from concentration-dependence assays performed using Xenopus laevis oocytes. Our methodology was verified by calculating Leu and L-phenylalanine (Phe) data in the presence of competitive substrates and/or inhibitors. Among 9 potentially expressed endogenous X. laevis oocyte Leu transporter species, activities of only the uniporters SLC43A2/LAT4 (and/or SLC43A1/LAT3) and the sodium symporter SLC6A19/B0AT1 were required to account for total uptake. Furthermore, Leu and Phe uptake by heterologously expressed human SLC6A14/ATB0,+ and SLC43A2/LAT4 was accurately calculated. This versatile systems biology approach is useful for analyses where the kinetics of each active protein species can be represented by the Hill equation. Furthermore, its applicable even in the absence of protein expression data. It could potentially be applied, for example, to quantify drug transporter activities in target cells to improve specificity.

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Essential amino acid transporter Lat4 (Slc43a2) is required for mouse development

Cited by 56 publications

References 51 publications

Transport of Iodothyronines by Human L-Type Amino Acid Transporters

Transport of Iodothyronines by Human L-Type Amino Acid Transporters

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

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

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