Protective roles of SLC30A3 against endoplasmic reticulum stress via ERK1/2 activation.
Protective roles of SLC30A3 against endoplasmic reticulum stress via ERK1/2 activation.
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DOI：
10.1016/j.bbrc.2016.09.119
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发表时间：
2016-10
影响因子：
3.1
通讯作者：
H. Kurita;Rika Okuda;Kazuki Yokoo;M. Inden;I. Hozumi
中科院分区：
文献类型：
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作者：
H. Kurita;Rika Okuda;Kazuki Yokoo;M. Inden;I. Hozumi
内质网（ER）应激被认为与阿尔茨海默病（AD）或肌萎缩侧索硬化症（ALS）等神经退行性疾病有关。既往研究表明AD患者前额皮质中SLC30A3水平降低。此外，我们还发现，ALS 患者的脑脊液中锌 (Zn) 水平升高，脊髓中 SLC30A3 水平降低。人们认为SLC30A3和ER应激都可能与AD和ALS的病因有关，但ER应激和SLC30A3之间的关系尚未阐明。因此我们研究了SLC30A3对抗ER应激的作用。衣霉素处理人神经母细胞瘤细胞系(SH-SY5Y)和人胚肾细胞系(HEK293)中SLC30A3mRNA的水平显着增加。与阴性对照（NC）细胞相比，siRNA 敲除的 SLC30A3 细胞在衣霉素处理下的细胞活力显着降低。在 SLC30A3 敲低细胞中，裂解的 caspase-3 水平显着增加，而在 NC 细胞中则没有。这些结果表明，SLC30A3 对 ER 应激诱导的毒性具有保护作用。前期研究表明SLC30A3以ERK1/2信号依赖的方式保护细胞免受氧化应激，因此我们测定了ER应激条件下SLC30A3敲除细胞中ERK1/2的活性。在 NC 细胞中，衣霉素处理后 ERK1/2 磷酸化水平显着增加，而在 SLC30A3 敲除细胞中则没有。 ERK1/2 通路被认为与 SLC30A3 对细胞应激（如 ER 应激）的防御作用有关。总之，本研究表明 SLC30A3 可能对 ER 应激发挥保护作用，这与 ERK1/2 激活有关。
Endoplasmic reticulum (ER) stress has been thought to be involved to neurodegenerative diseases such as Alzheimer's disease (AD) or Amyotrophic lateral sclerosis (ALS). The previous studies have shown that SLC30A3 level is decreased in prefrontal cortex of AD patients. In addition, we have shown that level of zinc (Zn) is increased in cerebrospinal fluid and SLC30A3 level is decreased in spinal cord of ALS patients. It was thought that both SLC30A3 and ER stress could be related to the cause of AD and ALS, however the relationship between ER stress and SLC30A3 has not been elucidated. Therefore we investigated that the role of SLC30A3 against ER stress. The level ofSLC30A3mRNA was significantly increased by tunicamycin treatment in human neuroblastoma cell line (SH-SY5Y) and human embryonic kidney cell line (HEK293). Cell viability under tunicamycin treatment was significantly decreased in SLC30A3 knockdown cells by siRNA in comparison with negative control (NC) cells. Cleaved caspase-3 level was significantly increased in SLC30A3 knockdown cells, not in NC cells. These results showed that SLC30A3 has a protective role to ER stress-induced toxicities. The previous study has shown that SLC30A3 protect cells from oxidative stress in ERK1/2 signal dependent manner, thus we determined the activity of ERK1/2 in SLC30A3 knockdown cells under ER stress condition. The level of ERK1/2 phosphorylation was significantly increased by tunicamycin treatment in NC cells, not in SLC30A3 knockdown cells. The ERK1/2 pathway is thought to have an association with defensive effects of SLC30A3 on cellular stress such as ER stress. In conclusion, this study suggested that SLC30A3 is supposed to play a protective role against ER stress, which is related to ERK1/2 activation.