CDNF induces the adaptive unfolded protein response and attenuates endoplasmic reticulum stress-induced cell death
CDNF induces the adaptive unfolded protein response and attenuates endoplasmic reticulum stress-induced cell death
复制标题
DOI：
10.1016/j.bbamcr.2018.08.012
复制
发表时间：
2018-11-01
影响因子：
5.1
通讯作者：
Estela Andres, Maria
中科院分区：
文献类型：
--
作者：
Arancibia, Duxan;Zamorano, Pedro;Estela Andres, Maria
脑多巴胺神经营养因子（CDNF）是一种神经营养因子，在多种神经退行性疾病的细胞和动物模型中具有保护作用。 CDNF保护作用的分子机制尚不清楚。许多神经退行性疾病与内质网 (ER) 的蛋白质稳态失调有关。蛋白质稳态的失败会产生内质网应激，触发未折叠蛋白反应（UPR），从长远来看，会诱导细胞死亡。适应性 UPR 通过减弱蛋白质合成、诱导伴侣表达和错误折叠蛋白质的降解来解决 ER 应激。由于 CDNF 是 ER 驻留蛋白，我们研究了 CDNF 的作用是否是调节 ER 蛋白质稳态。为此，我们确定了 CDNF 对毒胡萝卜素诱导的 HEK293-T 细胞和培养的海马神经元内质网应激的影响。我们的结果表明 CDNF 提高了暴露于毒胡萝卜素的 HEK293-T 细胞的活力。 CDNF 增加了 HEK293-T 细胞和神经元中早期 UPR 保护蛋白的水平，例如 BiP、ATF4、ATF6 和 XBP-1。相反，CDNF 的表达减弱了 HEK293-T 细胞和神经元中 ER 应激诱导的凋亡蛋白、CHOP 和裂解的 caspase-3。缺乏 ER 保留序列的突变 CDNF 无法抵御 ER 应激。总之，CDNF 通过诱导适应性 UPR 反应和抑制 ER 应激触发的细胞凋亡途径来调节 ER 中的蛋白质稳态。我们认为 CDNF 诱导的神经保护作用是通过调节 ER 蛋白质稳态介导的。
The Cerebral Dopamine Neurotrophic Factor (CDNF) is a neurotrophic factor that has a protective effect in cell and animal models of several neurodegenerative diseases. The molecular mechanism of the protective effect of CDNF is unclear. Many neurodegenerative diseases have been related to a proteostasis dysregulation in the endoplasmic reticulum (ER). A failure of proteostasis produces ER stress, triggering the unfolded protein response (UPR) and, in the long-term, induces cell death. An adaptive UPR solves ER stress by attenuating protein synthesis, inducing chaperones expression, and degradation of misfolded proteins. Since CDNF is an ER resident protein, we investigated whether the role of CDNF is to regulate ER proteostasis. To this end, we determined the effect of CDNF in thapsigargin-induced ER stress in HEK293-T cells and cultured hippocampal neurons. Our results show that CDNF improved the viability of HEK293-T cells exposed to thapsigargin. CDNF increased levels of protective proteins of the early UPR, such as BiP, ATF4, ATF6, and XBP-1 in both HEK293-T cells and neurons. Conversely, expression of CDNF attenuated ER stress-induced apoptotic proteins, CHOP and cleaved caspase-3 in HEK293-T cells and neurons. A mutant CDNF lacking the ER retention sequence failed to protect against ER stress. In conclusion, CDNF regulates proteostasis in the ER by inducing the adaptive UPR response and inhibiting apoptotic pathways triggered by ER stress. We propose that neuroprotection induced by CDNF is mediated by regulating ER proteostasis.