Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2.
Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2.
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DOI：
10.1042/cs20150554
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Jansson T
中科院分区：
文献类型：
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作者：
Rosario FJ;Dimasuay KG;Kanai Y;Powell TL;Jansson T
胎盘氨基酸转移的改变直接导致胎儿生长的改变，这增加了围产期并发症的风险，并在以后的生活中易患肥胖、糖尿病和心血管疾病。胎盘氨基酸转移严重依赖于滋养细胞质膜中特定转运蛋白的表达，滋养细胞是人胎盘的转运上皮。然而，调控这一过程的分子机制在很大程度上是未知的。Nedd4-2是一种泛素连接酶，催化蛋白质的泛素化，导致蛋白酶体降解。我们假设mTORC1的抑制通过激活Nedd4-2来减少人原代滋养细胞（PHT）的氨基酸摄取，从而增加转运蛋白泛素化，导致质膜转运蛋白表达减少。mTORC 1抑制增加Nedd4-2的表达，促进泛素化，降低质膜上SNAT2 （System A氨基酸转运体异构体）和LAT1 （System L氨基酸转运体异构体）的表达，导致细胞氨基酸摄取减少。Nedd4-2的沉默显著增加了SNAT2和LAT1向质膜的转运，从而刺激了细胞对氨基酸的摄取。通过沉默raptor抑制mTORC1未能减少Nedd4-2沉默后的氨基酸运输。总之，我们已经确定了mTORC1信号和泛素化之间的新联系，泛素化是一种常见的翻译后修饰。由于胎盘mTORC1在胎儿生长受限时被抑制，在胎儿过度生长时被激活，我们提出mTORC1和Nedd4-2调控胎盘氨基酸转运体泛素化是胎儿异常生长的分子机制。
Changes in placental amino acid transfer directly contribute to altered fetal growth, which increases the risk for perinatal complications and predisposes for the development of obesity, diabetes and cardiovascular disease later in life. Placental amino acid transfer is critically dependent on the expression of specific transporters in the plasma membrane of the trophoblast, the transporting epithelium of the human placenta. However, the molecular mechanisms regulating this process are largely unknown. Nedd4-2 is an ubiquitin ligase that catalyzes the ubiquitination of proteins, resulting in proteasomal degradation. We hypothesized that inhibition of mTORC1 decreases amino acid uptake in primary human trophoblast cells (PHT) by activation of Nedd4-2, which increases transporter ubiquitination resulting in decreased transporter expression in the plasma membrane. mTORC 1 inhibition increased the expression of Nedd4-2, promoted ubiquitination and decreased the plasma membrane expression of SNAT2 (an isoform of the System A amino acid transporter) and LAT1 (a System L amino acid transporter isoform), resulting in decreased cellular amino acid uptake. Nedd4-2 silencing markedly increased the trafficking of SNAT2 and LAT1 to the plasma membrane, which stimulated cellular amino acid uptake. mTORC1 inhibition by silencing of raptor failed to decrease amino acid transport following Nedd4-2 silencing. In conclusion, we have identified a novel link between mTORC1 signaling and ubiquitination, a common posttranslational modification. Because placental mTORC1 is inhibited in fetal growth restriction and activated in fetal overgrowth, we propose that regulation of placental amino acid transporter ubiquitination by mTORC1 and Nedd4-2 constitutes a molecular mechanisms underlying abnormal fetal growth.