Zinc oxide nanoparticles harness autophagy to induce cell death in lung epithelial cells.
Zinc oxide nanoparticles harness autophagy to induce cell death in lung epithelial cells.
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氧化锌纳米颗粒利用自噬诱导肺上皮细胞死亡
DOI：
10.1038/cddis.2017.337
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发表时间：
2017-07-27
影响因子：
9
通讯作者：
Zou Z
中科院分区：
文献类型：
--
作者：
Zhang J;Qin X;Wang B;Xu G;Qin Z;Wang J;Wu L;Ju X;Bose DD;Qiu F;Zhou H;Zou Z
虽然氧化锌纳米颗粒（ZnONPs）被广泛使用，但它们对人体的毒性引起了关注。已有研究表明活性氧（reactive oxygen species， ROS）和自噬参与了ZnONPs的细胞毒性，但自噬和ROS之间的调控机制尚不清楚。在此，我们全面研究了znonps处理的肺上皮细胞自噬的调控机制以及自噬与ROS之间的联系。我们证明了ZnONPs可以诱导自噬，这一过程可以促进ZnONPs在溶酶体中的溶解，释放锌离子。随后，从ZnONPs释放的锌离子不仅能损伤溶酶体，导致自噬通量受损，还能损伤线粒体。自噬通量受损导致受损线粒体积聚，产生过多ROS导致细胞死亡。我们进一步证明，通过药物抑制剂或小干扰RNA （siRNA）介导的Beclin-1和amp激活的蛋白激酶的敲低抑制自噬可以改善znonps诱导的细胞死亡。此外，我们发现溶酶体相关膜蛋白1/2 （LAMP-1/2）在ZnONPs处理后表现出异常的表达模式，这是溶酶体晚期内体/溶酶体中最丰富的高度糖基化蛋白。有趣的是，敲低LAMP-2而非敲低LAMP-1可加剧ZnONPs诱导的ROS生成和细胞死亡。同时，LAMP-2过表达可减轻ZnONPs诱导的细胞死亡，提示LAMP-2与ZnONPs诱导的这种毒性表型有关。我们的研究结果表明，自噬功能障碍可能导致ZnONPs在肺上皮细胞中产生过多的ROS，这表明调节自噬过程可以最小化ZnONPs相关的毒性。
Although zinc oxide nanoparticles (ZnONPs) are widely used, they have raised concerns of toxicity in humans. Previous studies have indicated that reactive oxygen species (ROS) and autophagy are involved in the cytotoxicity of ZnONPs, but the regulatory mechanisms between autophagy and ROS remain to be elucidated. Herein, we comprehensively investigated the regulatory mechanism of autophagy and the link between autophagy and ROS in ZnONPs-treated lung epithelial cells. We demonstrated that ZnONPs could induce autophagy, and this process could enhance the dissolution of ZnONPs in lysosomes to release zinc ions. Sequentially, zinc ions released from ZnONPs were able to damage not only lysosomes, leading to impaired autophagic flux, but also mitochondria. Impaired autophagic flux resulted in the accumulation of damaged mitochondria, which could generate excessive ROS to cause cell death. We further demonstrated that the inhibition of autophagy by either pharmacological inhibitors or small interfering RNA (siRNA)-mediated knockdown of Beclin-1 and AMP-activated protein kinase could ameliorate ZnONPs-induced cell death. Moreover, we found that lysosomal-associated membrane protein 1/2 (LAMP-1/2), which were the most abundant highly glycosylated protein in late endosomes/lysosomes, exhibited aberrant expression pattern upon treatment with ZnONPs. Intriguingly, LAMP-2 knockdown, but not LAMP-1 knockdown, could exacerbate the ROS generation and cell death induced by ZnONPs treatment. Meanwhile, LAMP-2 overexpression alleviated ZnONPs-induced cell death, suggesting that LAMP-2 was linked to this toxic phenotype induced by ZnONPs. Our results indicate that autophagic dysfunction could contribute to excessive ROS generation upon treatment with ZnONPs in lung epithelial cells, suggesting that modulating the autophagy process would minimize ZnONPs-associated toxicity.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
5.8
作者：
Li X;Yan J;Wang L;Xiao F;Yang Y;Guo X;Wang H
通讯作者：
Wang H
DOI：
10.1164/rccm.201002-0185oc
发表时间：
2010-12-01
影响因子：
24.7
作者：
Kim, Yong Ho;Fazlollahi, Farnoosh;Crandall, Edward D.
通讯作者：
Crandall, Edward D.