Early-stage autophagy protects nucleus pulposus cells from glucose deprivation-induced degeneration via the p-eIF2α/ATF4 pathway
Early-stage autophagy protects nucleus pulposus cells from glucose deprivation-induced degeneration via the p-eIF2α/ATF4 pathway
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DOI：
10.1016/j.biopha.2017.02.074
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发表时间：
2017-05-01
影响因子：
7.5
通讯作者：
Liu, Xiaodong
中科院分区：
文献类型：
--
作者：
Chang, Hongze;Cai, Feng;Liu, Xiaodong
自噬是细胞生存的双刃剑，但其对髓核（NP）细胞的影响尚不清楚。本研究探讨了自噬在营养剥夺条件下NP细胞存活中的作用及其分子机制。葡萄糖限制诱导NP细胞的时间依赖性形态学变化、蛋白多糖降解和凋亡。葡萄糖剥夺触发了早期自噬的激活，这明显表现为LC 3-II和ATG 12-ATG 5表达以及GFP-LC 3斑点数量的增加。重要的是，在早期时间点，自噬抑制剂3-MA显著增强NP细胞的凋亡，表明早期自噬保护细胞免受葡萄糖剥夺。有趣的是，p-eIF 2 α/ATF 4未折叠蛋白反应途径在缺乏葡萄糖的NP细胞中被激活，并且ATF 4的缺乏减弱了早期自噬的激活并增加了凋亡。ATF 4沉默还抑制了活性氧（ROS）的晚期积累和细胞凋亡。总之，我们的研究结果表明，内质网应激，活性氧的产生，和早期阶段的自噬诱导的葡萄糖剥夺在NP细胞之间的相互作用。这些发现可能为退行性椎间盘疾病的治疗提供一种治疗策略。(C)2017年Elsevier Masson SAS。All rights reserved.
Autophagy is a double-edged sword in cellular survival, but its effects on nucleus pulposus (NP) cells are yet to be clarified. This study explored the role and molecular mechanisms of autophagy in the survival of NP cells under nutrient deprivation. Glucose limitation induced time-dependent morphological changes, proteoglycan degradation, and apoptosis in NP cells. Glucose deprivation triggered the activation of earlystage autophagy, evident as increases in LC3-II and ATG12-ATG5 expression and the number of GFP-LC3 puncta. Importantly, at early time points, the autophagy inhibitor 3-MA significantly enhanced the apoptosis of NP cells, suggesting that early-stage autophagy protects cells against glucose deprivation. Interestingly, the p-eIF2 alpha/ATF4 unfolded protein response pathway was activated in NP cells deprived of glucose, and a deficiency in ATF4 attenuated the activation of early-stage autophagy and increased apoptosis. ATF4 silencing also inhibited the late-stage accumulation of reactive oxygen species (ROS) and apoptosis. Together, our results demonstrate an interplay between endoplasmic reticulum stress, ROS production, and the early-stage autophagy induced by glucose deprivation in NP cells. These findings may provide a therapeutic strategy for the treatment of degenerative intervertebral disc disease. (C) 2017 Elsevier Masson SAS. All rights reserved.