Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain.
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain.
Cell Commun Signal. 2023 Nov 13;21(1):326. doi: 10.1186/s12964-023-01352-5.
The placentas from newborns that are small for gestational age (SGA; birth weight < -2 SD for gestational age) may display multiple pathological characteristics. A key determinant of fetal growth and, therefore, birth weight is placental amino acid transport, which is under the control of the serine/threonine kinase mechanistic target of rapamycin (mTOR). The effects of endoplasmic reticulum (ER) stress on the mTOR pathway and the levels of amino acid transporters are not well established.
Placentas from SGA and appropriate for gestational age (AGA) newborns and the human placental BeWo cell line exposed to the ER stressor tunicamycin were used.
We detected a significant increase in the levels of C/EBP homologous protein (CHOP) in the placentas from SGA newborns compared with those from AGA newborns, while the levels of other ER stress markers were barely affected. In addition, placental mTOR Complex 1 (mTORC1) activity and the levels of the mature form of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) were also reduced in the SGA group. Interestingly, CHOP has been reported to upregulate growth arrest and DNA damage-inducible protein 34 (GADD34), which in turn suppresses mTORC1 activity. The GADD34 inhibitor guanabenz attenuated the increase in CHOP protein levels and the reduction in mTORC1 activity caused by the ER stressor tunicamycin in the human placental cell line BeWo, but it did not recover mature SNAT2 protein levels, which might be reduced as a result of defective glycosylation.
Collectively, these data reveal that GADD34A activity and glycosylation are key factors controlling mTORC1 signaling and mature SNAT2 levels in trophoblasts, respectively, and might contribute to the SGA condition. Video Abstract.
小于胎龄儿（SGA；出生体重低于相应胎龄的-2 个标准差）的胎盘可能表现出多种病理特征。胎儿生长的关键决定因素，也是出生体重的关键决定因素，是胎盘氨基酸转运，而这受丝氨酸/苏氨酸激酶雷帕霉素靶蛋白（mTOR）的控制。内质网（ER）应激对 mTOR 通路和氨基酸转运体水平的影响尚未得到充分证实。
使用 SGA 和适当胎龄（AGA）新生儿的胎盘和人胎盘 BeWo 细胞系暴露于内质网应激剂衣霉素。
与 AGA 新生儿相比，我们在 SGA 新生儿的胎盘组织中检测到 C/EBP 同源蛋白（CHOP）水平显著增加，而其他 ER 应激标志物的水平几乎没有受到影响。此外，SGA 组胎盘 mTOR 复合物 1（mTORC1）活性和成熟形式的氨基酸转运体钠偶联中性氨基酸转运体 2（SNAT2）水平也降低。有趣的是，CHOP 已被报道上调生长停滞和 DNA 损伤诱导蛋白 34（GADD34），后者反过来抑制 mTORC1 活性。GADD34 抑制剂胍那苄可减轻内质网应激剂衣霉素引起的 BeWo 人胎盘细胞系中 CHOP 蛋白水平升高和 mTORC1 活性降低，但不能恢复成熟 SNAT2 蛋白水平，这可能是由于糖基化缺陷所致。
总之，这些数据表明 GADD34A 活性和糖基化分别是控制滋养细胞中 mTORC1 信号和成熟 SNAT2 水平的关键因素，可能导致 SGA 状态。
