Lysosomal thiol reductase negatively regulates autophagy by altering glutathione synthesis and oxidation
Lysosomal thiol reductase negatively regulates autophagy by altering glutathione synthesis and oxidation
复制标题
DOI：
10.1016/j.freeradbiomed.2011.05.015
复制
发表时间：
2011-08-01
影响因子：
7.4
通讯作者：
Maric, Maja
中科院分区：
文献类型：
--
作者：
Chiang, Hao-Sen;Maric, Maja
氧化还原调节对于许多细胞功能是至关重要的，并且已经涉及若干疾病的病因学和进展，例如心血管疾病、神经退行性疾病和癌症。已经显示，在不存在γ-干扰素诱导型溶酶体硫醇还原酶（GILT）的情况下，细胞处于增加的氧化应激下，具有更高的超氧化物水平和降低的稳定性、表达和线粒体锰超氧化物歧化酶（SOD 2）的功能。在这里，我们进一步阐明GILT在氧化应激的稳态调节中的作用。我们发现，GILT缺陷的成纤维细胞表现出谷胱甘肽水平降低，GSSG/GSH比例向氧化形式的转变，并积累功能障碍的线粒体。涉及Erk 1/2激活和核高迁移率族蛋白1（HMGB 1）蛋白胞质易位的氧化还原敏感途径都被激活，并且与GILT-/-成纤维细胞中增加的自噬相关。我们假设这些事件是负责降解受损的线粒体和线粒体SOD 2在GILT的情况下。据我们所知，这是第一次溶酶体酶与细胞内的整体效应有关。爱思唯尔公司出版
Redox regulation is critical for a number of cellular functions and has been implicated in the etiology and progression of several diseases, such as cardiovascular diseases, neurodegenerative diseases, and cancer. It has been shown that, in the absence of gamma-interferon inducible lysosomal thiol reductase (GILT), cells are under increased oxidative stress with higher superoxide levels and decreased stability, expression, and function of mitochondrial manganese superoxide dismutase (SOD2). Here, we further elucidate the role of GILT in the homeostatic regulation of oxidative stress. We show that GILT-deficient fibroblasts exhibit reduced glutathione levels, shift in GSSG/GSH ratio toward the oxidized form, and accumulate dysfunctional mitochondria. Redox-sensitive pathways involving Erk1/2 activation and nuclear high mobility group box 1 (HMGB1) protein cytosolic translocation are both activated and associated with increased autophagy in GILT-/- fibroblasts. We hypothesize that these events are responsible for degrading the damaged mitochondria and mitochondrial SOD2 in the absence of GILT. This is the first time to our knowledge that a lysosomal enzyme has been implicated in global effects within the cell. Published by Elsevier Inc.