背景:胎龄小的新生儿胎盘(SGA;胎龄出生体重<-2SD)可能表现出多种病理特征。胎儿生长的关键决定因素,因此,出生体重是胎盘氨基酸的转运,其处于雷帕霉素(mTOR)的丝氨酸/苏氨酸激酶机制靶标的控制之下。内质网(ER)应激对mTOR途径和氨基酸转运蛋白水平的影响尚未完全确定。
方法:使用来自SGA和适合胎龄(AGA)新生儿的胎盘和暴露于ER应激膜霉素的人胎盘BeWo细胞系。
结果:我们检测到SGA新生儿胎盘中的C/EBP同源蛋白(CHOP)水平与AGA新生儿相比显著增加,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)活性和氨基酸转运蛋白钠偶联中性氨基酸转运蛋白2(SNAT2)成熟形式的水平也降低。有趣的是,据报道,CHOP可以上调生长停滞和DNA损伤诱导蛋白34(GADD34),进而抑制mTORC1活性。GADD34抑制剂guanabenz减弱了人胎盘细胞系BeWo中由ER应激源衣霉素引起的CHOP蛋白水平的增加和mTORC1活性的降低,但它没有恢复成熟的SNAT2蛋白水平,可能由于糖基化缺陷而减少。
结论:总的来说,这些数据表明,GADD34A活性和糖基化是控制滋养细胞中mTORC1信号传导和成熟SNAT2水平的关键因素,分别,并可能导致SGA状况。视频摘要。
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.