Activation of chaperone-mediated autophagy during oxidative stress
Activation of chaperone-mediated autophagy during oxidative stress
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DOI：
10.1091/mbc.e04-06-0477
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发表时间：
2004-11-01
影响因子：
3.3
通讯作者：
Cuervo, AM
中科院分区：
文献类型：
--
作者：
Kiffin, R;Christian, C;Cuervo, AM
氧化损伤的蛋白质随着年龄的增长在几乎所有类型的细胞和组织中积累。伴侣介导的自噬(CMA)是一种选择性地降解溶酶体中胞浆蛋白的途径，其活性随着年龄的增长而降低。我们分析了CMA在大鼠肝脏和培养的小鼠成纤维细胞中清除氧化蛋白的可能参与。此外，当CMA底物被氧化时，更有效地内化到溶酶体中，我们发现在氧化应激期间CMA的结构性激活。氧化诱导的CMA激活与溶酶体转位复合体的几个组分的高水平相关，特别是底物摄取所需的管腔伴侣蛋白，以及溶酶体膜蛋白(LAMP)2a型的高水平，以前被认为是这一途径的受体。与营养应激时CMA激活的机制不同，CMA的激活不需要受体的从头合成，而氧化诱导的CMA激活是通过转录上调LAMP2A实现的。我们的结论是，CMA在氧化应激过程中被激活，在这些条件下，这一途径的较高活性，以及被氧化蛋白质被溶酶体摄取的更高敏感性，都有助于有效地去除被氧化蛋白质。
Oxidatively damaged proteins accumulate with age in almost all cell types and tissues. The activity of chaperone-mediated autophagy (CMA), a selective pathway for the degradation of cytosolic proteins in lysosomes, decreases with age. We have analyzed the possible participation of CMA in the removal of oxidized proteins in rat liver and cultured mouse fibroblasts. Added to the fact that CMA substrates, when oxidized, are more efficiently internalized into lysosomes, we have found a constitutive activation of CMA during oxidative stress. Oxidation-induced activation of CMA correlates with higher levels of several components of the lysosomal translocation complex, but in particular of the lumenal chaperone, required for substrate uptake, and of the lysosomal membrane protein (lamp) type 2a, previously identified as a receptor for this pathway. In contrast with the well characterized mechanism of CMA activation during nutritional stress, which does not require de novo synthesis of the receptor, oxidation-induced activation of CMA is attained through transcriptional up-regulation of lamp2a. We conclude that CMA is activated during oxidative stress and that the higher activity of this pathway under these conditions, along with the higher susceptibility of the oxidized proteins to be taken up by lysosomes, both contribute to the efficient removal of oxidized proteins.