Lorenzon-Ojea Aline R, Guzzo Cristiane R, Kapidzic Mirhan, Fisher Susan J, Bevilacqua Estela
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil Department of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California San Francisco, San Francisco, California.
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Biol Reprod. 2016 Aug;95(2):41. doi: 10.1095/biolreprod.115.138164. Epub 2016 Jun 22.
Endoplasmic reticulum (ER) stress results from changes in ER homeostasis and folding of proteins. ER stress initiates cellular adaptive mechanisms to rescue cell homeostasis or, if that does not work, to elicit apoptosis. We have previously shown that mouse SDF2 is sublocalized in the ER, is ubiquitously expressed, and shows strong similarities with stromal cell-derived factor (SDF) 2L1 and SDF2-like from Arabidopsis, ER proteins involved in chaperone network and protein folding. Thus, we hypothesized that SDF2 plays a role in the ER stress and unfolded protein response. In this study, we investigated the possible role of SDF2 in the human placenta. Expression of SDF2 was present throughout gestation and was expressed by several cell types. Second-trimester cytotrophoblast cells (CTBs) in the differentiation process, monitored through chorionic gonadotropin production, showed upregulation of SDF2 protein. SDF2 expression, however, was significantly diminished in placentas from neonates small for gestational age and in hypoxic in vitro conditions (P ≤ 0.001, 2% O2), suggesting a link with cellular stress. ER stress-induced cells-CTB and BeWo-also showed SDF2 downregulation in different time points, emphasizing this relationship. SDF2 downregulation was also followed by an increase in binding immunoglobulin protein (BiP) expression, an ER protein-associated chaperone acting as a sensor for misfolded proteins and an ER stress cell survival marker. In line with this, SDF2 siRNA resulted in significant anticipation of BiP expression. Downregulation of SDF2 also interfered with C/EBP homologous protein expression, one of the highest inducible genes during ER stress. These findings suggest that SDF2 may be an important regulatory factor by which trophoblast cells can control cell survival under ER stress. In conclusion, this study identifies a novel factor with the ability to interfere with ER stress proteins, which may contribute to the understanding of ER stress associated with placental-related diseases of pregnancy.
内质网（ER）应激源于内质网稳态的改变和蛋白质折叠。内质网应激启动细胞适应性机制以恢复细胞稳态，若此机制无效，则引发细胞凋亡。我们之前已经表明，小鼠SDF2定位于内质网，广泛表达，并且与基质细胞衍生因子（SDF）2L1以及拟南芥中的SDF2样蛋白具有很强的相似性，这些内质网蛋白参与伴侣网络和蛋白质折叠。因此，我们推测SDF2在内质网应激和未折叠蛋白反应中发挥作用。在本研究中，我们调查了SDF2在人胎盘中可能发挥的作用。SDF2在整个妊娠期均有表达，并且由多种细胞类型表达。通过绒毛膜促性腺激素产生来监测的妊娠中期细胞滋养层细胞（CTB）在分化过程中显示SDF2蛋白上调。然而，在小于胎龄新生儿的胎盘以及低氧体外条件下（P≤0.001，2%氧气），SDF2的表达显著降低，这表明其与细胞应激有关。内质网应激诱导的细胞——CTB和BeWo——在不同时间点也显示SDF2下调，强调了这种关系。SDF2下调之后还伴随着结合免疫球蛋白蛋白（BiP）表达的增加，BiP是一种与内质网蛋白相关的伴侣蛋白，作为错误折叠蛋白的传感器和内质网应激细胞存活标志物。与此一致的是，SDF2 siRNA导致BiP表达显著提前。SDF2的下调也干扰了C/EBP同源蛋白的表达，C/EBP同源蛋白是内质网应激期间诱导程度最高的基因之一。这些发现表明，SDF2可能是一种重要的调节因子，滋养层细胞可通过它来控制内质网应激下的细胞存活。总之，本研究鉴定出一种能够干扰内质网应激蛋白的新因子，这可能有助于理解与妊娠胎盘相关疾病有关的内质网应激。
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