Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription.
Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription.
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DOI：
10.1016/j.redox.2018.04.001
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发表时间：
2018-06
期刊：
影响因子：
11.4
通讯作者：
Grumbach IM
中科院分区：
文献类型：
--
作者：
Pennington SM;Klutho PR;Xie L;Broadhurst K;Koval OM;McCormick ML;Spitz DR;Grumbach IM
氧化甲硫氨酸的还原正在成为主要的蛋白质修复途径。甲硫氨酸亚砜还原酶A（MsrA）的缺乏加剧了由氧化应激增加驱动的心血管疾病表型。然而，在没有过度氧化应激的情况下，MsrA对维持细胞稳态的作用还不太清楚。MsrA组成性基因缺失增加了含p62蛋白聚集体的形成，激活了自噬，并减少了血管平滑肌细胞（VSMC）中的凋亡标志物。Keap 1与p62的相关性在MsrA-/- VSMC中增强。Keap 1靶向调节抗氧化基因的转录因子Nrf 2，用于蛋白酶体降解。然而，在MsrA-/- VSMC中，Nrf 2与Keap 1的关联减弱。而在MsrA-/- VSMC中Nrf 2 mRNA水平没有降低，我们检测到Nrf 2的泛素化降低，在没有氧化应激生化标志物的情况下，总Nrf 2蛋白相应增加。此外，核定位的Nrf 2增加下MsrA缺陷，导致Nrf 2依赖的转录活性上调。因此，转录，蛋白质水平和谷氨酸-半胱氨酸连接酶和谷胱甘肽还原酶的酶活性大大增强MsrA-/- VSMC。我们的研究结果表明，在没有增加氧化应激的情况下，蛋氨酸氧化的逆转是维持细胞稳态所必需的。这些数据提供了在MsrA缺失的情况下自噬和Nrf 2激活之间的第一个联系。随着MsrA缺失，含有p62的细胞内蛋白质聚集体增加。自噬在增殖的MsrA-/-平滑肌细胞中增加。Keap-1与p62的增加的关联在MsrA-/-细胞中解抑制Nrf 2。MsrA-/-细胞中的Nrf 2活化在不增加氧化应激的情况下发生。
Reduction of oxidized methionines is emerging as a major protein repair pathway. The lack of methionine sulfoxide reductase A (MsrA) exacerbates cardiovascular disease phenotypes driven by increased oxidative stress. However, the role of MsrA on maintaining cellular homeostasis in the absence of excessive oxidative stress is less well understood. Constitutive genetic deletion of MsrA increased formation of p62-containing protein aggregates, activated autophagy, and decreased a marker of apoptosis in vascular smooth muscle cells (VSMC). The association of Keap1 with p62 was augmented in MsrA-/- VSMC. Keap1 targets the transcription factor Nrf2, which regulates antioxidant genes, for proteasomal degradation. However, in MsrA-/- VSMC, the association of Nrf2 with Keap1 was diminished. Whereas Nrf2 mRNA levels were not decreased in MsrA-/- VSMC, we detected decreased ubiquitination of Nrf2 and a corresponding increase in total Nrf2 protein in the absence of biochemical markers of oxidative stress. Moreover, nuclear-localized Nrf2 was increased under MsrA deficiency, resulting in upregulation of Nrf2-dependent transcriptional activity. Consequently, transcription, protein levels and enzymatic activity of glutamate-cysteine ligase and glutathione reductase were greatly augmented in MsrA-/- VSMC. Our findings demonstrate that reversal of methionine oxidation is required for maintenance of cellular homeostasis in the absence of increased oxidative stress. These data provide the first link between autophagy and activation of Nrf2 in the setting of MsrA deletion. With MsrA deletion, p62-containing intracellular protein aggregates are increased. Autophagy is increased in proliferating MsrA-/- smooth muscle cells. Increased association of Keap-1 with p62 derepresses Nrf2 in MsrA-/- cells. Nrf2 activation in MsrA-/- cells occurs without increased oxidative stress.
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DOI：
10.1073/pnas.94.18.9932
发表时间：
1997-09-02
影响因子：
11.1
作者：
Ciorba, MA;Heinemann, SH;Hoshi, T
通讯作者：
Hoshi, T
影响因子：
2.9
作者：
GRIFFITH, OW
通讯作者：
GRIFFITH, OW
影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
影响因子：
64.5
作者：
Erickson, Jeffrey R.;Joiner, Mei-ling A.;Anderson, Mark E.
通讯作者：
Anderson, Mark E.