Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta

Ritchie, James W.A.; Taylor, Peter M.

doi:10.1042/0264-6021:3560719

Cited by 74 publications

(49 citation statements)

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“…LAT1 and 4F2hc colocalize in the apical and basal surfaces of a single syncytiotrophoblast layer in the human term placenta (22,25,26). We found that LAT1, together with 4F2hc, is located in the apical surface of SynT-I and the basal surface of SynT-II in mature mouse placentas (Fig.…”

Section: Discussionmentioning

confidence: 74%

“…In contrast, LAT1 protein expression has been reported only in limited normal tissues/organs such as the blood-brain barrier and placenta (22)(23)(24)(25). In the human term placenta, LAT1 has been colocalized with 4F2hc at two polarized plasma membrane domains of the syncytiotrophoblast, i.e., the maternally facing apical membrane and the fetally facing basal membrane (22,25,26), implying the importance of LAT1-4F2hc heterodimer in the maternofetal transfer of amino acids. Based on studies using primary human trophoblasts, it has been proposed that abrogated cell surface localization of LAT1 may be implicated in intrauterine growth restriction (IUGR) (27,28), in which placental amino acid transport is impaired (29,30).…”

mentioning

confidence: 95%

“…It is now widely accepted that LAT1 is upregulated in various types of cancers to support tumor growth by providing cancer cells with amino acids (20,21). In contrast, LAT1 protein expression has been reported only in limited normal tissues/organs such as the blood-brain barrier and placenta (22)(23)(24)(25). In the human term placenta, LAT1 has been colocalized with 4F2hc at two polarized plasma membrane domains of the syncytiotrophoblast, i.e., the maternally facing apical membrane and the fetally facing basal membrane (22,25,26), implying the importance of LAT1-4F2hc heterodimer in the maternofetal transfer of amino acids.…”

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confidence: 99%

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Essential Roles of L-Type Amino Acid Transporter 1 in Syncytiotrophoblast Development by Presenting Fusogenic 4F2hc

Ohgaki

Ohmori

Hara

et al. 2017

Molecular and Cellular Biology

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The layers of the epithelial syncytium, i.e., syncytiotrophoblasts, differentiate from chorionic trophoblasts via cell fusion and separate maternal and fetal circulations in hemochorial placentas. L-type amino acid transporter 1 (LAT1) and its covalently linked ancillary subunit 4F2hc are colocalized on both maternal and fetal surfaces of syncytiotrophoblasts, implying their roles in amino acid transfer through the placental barrier. In this study, LAT1 knockout, in addition, revealed a novel role of LAT1 in syncytiotrophoblast development. LAT1 at midgestation was selectively expressed in trophoblastic lineages in the placenta, exclusively as a LAT1-4F2hc heterodimer. In LAT1 homozygous knockout mice, chorionic trophoblasts remained largely mononucleated, and the layers of syncytiotrophoblasts were almost completely absent. The amount of 4F2hc protein, which possesses a fusogenic function in trophoblastic cells, as well as in virus-infected cells, was drastically reduced by LAT1 knockout, with less affecting the mRNA level. Knockdown of LAT1 in trophoblastic BeWo cells also reduced 4F2hc protein and suppressed forskolin-induced cell fusion. These results demonstrate a novel fundamental role of LAT1 to support the protein expression of 4F2hc via a chaperone-like function in chorionic trophoblasts and to promote syncytiotrophoblast formation by contributing to cell fusion in the developing placenta.

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Section: Discussionmentioning

confidence: 74%

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confidence: 95%

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confidence: 99%

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Essential Roles of L-Type Amino Acid Transporter 1 in Syncytiotrophoblast Development by Presenting Fusogenic 4F2hc

Ohgaki

Ohmori

Hara

et al. 2017

Molecular and Cellular Biology

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“…At the outer BRB, the main amino acid flux is from the circulating blood to the retina. The position of LAT2 at the outer BRB seems to be analogous to its localization on the efflux side of (re)absorbing epithelia, 10,31 and LAT1 may be expressed on the opposite side (blood side) of the outer BRB, although further studies are necessary to investigate the localization and protein expression level of LAT1 and LAT2 at the outer BRB.…”

Section: Discussionmentioning

confidence: 99%

Involvement of LAT1 and LAT2 in the high- and low-affinity transport of L-leucine in human retinal pigment epithelial cells (ARPE-19 cells)

Yamamoto

Akanuma

Tachikawa

et al. 2010

Journal of Pharmaceutical Sciences

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“…2 A schematic representation of the role of tryptophan transport in human placental indoleamine-2,3-dioxygenase-mediated lymphocyte regulation. The possible molecular basis (see [10,12]) of the relevant heterodimeric transporters is shown as leucine will act to energize tryptophan efflux across this membrane into the fetal circulation.…”

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confidence: 99%

The physiology of immune evasion during pregnancy; the critical role of placental tryptophan metabolism and transport

Kudo

2001

Pfl�gers Archiv European Journal of Physiology

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Since the embryo and its associated extra-embryonic tissue express genes that are derived from both maternal and paternal alleles, and since this conceptus embeds within maternal uterine endometrium as a "graft" for the whole of the rest of pregnancy, it is unsurprising that much research into the "fetal allograft" problem [5] has been undertaken by reproductive immunologists over the last 40 years. Remarkably a quite unexpected finding that may resolve this question was published in 1998. Munn and colleagues [9] showed (in mice) that a tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase [14] was required to be functioning presumably in the placenta if the expected immune response (which they showed would otherwise necessarily result in fetal rejection) was to be averted. Table 1 indicates their key experimental finding.The strength of the experimental design comes from the availability of both a specific pharmacological inhibitor (1-methyl-tryptophan) [2]of the indoleamine 2,3-dioxygenase enzyme and "smart" transgenic animals that provide unambiguous controls. Since for allogeneic matings (but not for syngeneic ones, where no immunological problems arise) pregnancies were successful only in animals with normally functioning placental indoleamine 2,3-dioxygenase, this seminal paper did not resolve how tryptophan metabolism is responsible for averting the immune response to pregnancy. Subsequently Munn et al. [8] provided strong evidence that indoleamine 2,3-dioxygenase, simply through localized tryptophan depletion, is able to suppress T lymphocyte proliferation and hence produce "immunosuppression by starvation" . Figure 1A shows that indeed the ability of human T cells to respond to a stimulus such as that produced by the nonspecific mitogen PHA is uniquely and absolutely dependent on the presence of (low concentrations of) tryptophan. It is not yet clear how this tryptophan-dependent restriction of T cell proliferation is brought about, but it is without doubt a novel and important aspect of T cell biology. However, of general interest here is the physiological context in which this key enzyme, indoleamine 2,3-dioxygenase, works: how can the placenta play this central role in regulating the maternal immune response mounted against it while at the same time allowing normal fetal nutrition?In pregnant women indoleamine 2,3-dioxygenase is expressed in the placenta particularly in the syncytiotrophoblast, the fetal-derived component that is in direct contact with the maternal endometrium during early pregnancy (including implantation) and subsequently later in pregnancy with the maternal circulation flowing through the intervillus space. (Although increased maternal tryptophan catabolism and production of the indoleamine 2,3-dioxygenase product kyneurine was observed by Schrocksnadel et al. [11], unsurprisingly these investigators did not at that time realize the possible significance of these findings.) However, the enzyme indoleamine 2,3-dioxygenase is cytoplasmic, which immediately raises two interesting...

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Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta

Cited by 74 publications

References 27 publications

Essential Roles of L-Type Amino Acid Transporter 1 in Syncytiotrophoblast Development by Presenting Fusogenic 4F2hc

Essential Roles of L-Type Amino Acid Transporter 1 in Syncytiotrophoblast Development by Presenting Fusogenic 4F2hc

Involvement of LAT1 and LAT2 in the high- and low-affinity transport of L-leucine in human retinal pigment epithelial cells (ARPE-19 cells)

The physiology of immune evasion during pregnancy; the critical role of placental tryptophan metabolism and transport

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