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

ABSTRACT: 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.

SUBMITTER: Ohgaki R

PROVIDER: S-EPMC5440655 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Ohgaki Ryuichi R Ohmori Takahiro T Hara Saori S Nakagomi Saya S Kanai-Azuma Masami M Kaneda-Nakashima Kazuko K Okuda Suguru S Nagamori Shushi S Kanai Yoshikatsu Y

Molecular and cellular biology 20170516 11

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 ro ...[more]

PMID: 28320871

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Project description:The cationic amino acid arginine, due to its positive charge, is usually accumulated in the cytosol. Nevertheless, arginine has to be released by a number of cell types, e.g. kidney cells, which supply other organs with this amino acid, or the endothelial cells of the blood-brain barrier which release arginine into the brain. Arginine release in mammalian cells can be mediated by two different transporters, y(+)LAT1 and y(+)LAT2. For insertion into the plasma membrane, these transporters have to be associated with the type-II membrane glycoprotein 4F2hc [Torrents, Estevez, Pineda, Fernandez, Lloberas, Shi, Zorzano and Palacin (1998) J. Biol. Chem. 273, 32437-32445]. The present study elucidates the function and distribution of y(+)LAT2. In contrast to y(+)LAT1, which is expressed mainly in kidney epithelial cells, lung and leucocytes, y(+)LAT2 has a wider tissue distribution, including brain, heart, testis, kidney, small intestine and parotis. When co-expressed with 4F2hc in Xenopus laevis oocytes, y(+)LAT2 mediated uptake of arginine, leucine and glutamine. Arginine uptake was inhibited strongly by lysine, glutamate, leucine, glutamine, methionine and histidine. Mutual inhibition was observed when leucine or glutamine was used as substrate. Inhibition of arginine uptake by neutral amino acids depended on the presence of Na(+), which is a hallmark of y(+)LAT-type transporters. Although arginine transport was inhibited strongly by glutamate, this anionic amino acid was only weakly transported by 4F2hc/y(+)LAT2. Amino acid transport via 4F2hc/y(+)LAT2 followed an antiport mechanism similar to the other members of this new family. Only preloaded arginine could be released in exchange for extracellular amino acids, whereas marginal release of glutamine or leucine was observed under identical conditions. These results indicated that arginine has the highest affinity for the intracellular binding site and that arginine release may be the main physiological function of this transporter.

Dataset Information

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

Publications

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

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