KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity.
KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity.
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DOI：
10.1042/bj20150568
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发表时间：
2015-08-01
期刊：
影响因子：
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通讯作者：
Zhang J
中科院分区：
文献类型：
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作者：
Dodson M;Redmann M;Rajasekaran NS;Darley-Usmar V;Zhang J
维持细胞氧化还原状态以允许细胞信号发生需要调节氧化剂和硫醇还原网络的控制产生，以允许蛋白质硫醇的特定调控翻译后修饰。氧化应激假说抓住了过量产生氧化剂可能是蛋白质毒性的概念，但未能预测到最近的发现，即Keap1-NRF2系统的过度激活也会导致蛋白质毒性。此外，Keap1-NRF2持续激活硫醇氧化还原网络，通过缩短正常新陈代谢或细胞信号所需的氧化后修饰的寿命，诱导还原应激。在这种背景下，为什么抗氧化剂或抗氧化剂途径的过度激活与亲电疗法可能是有害的，现在变得越来越清楚。这进一步表明，自噬-溶酶体途径在保护细胞免受氧化还原应激诱导的蛋白毒性方面特别重要，因为它可以降解氧化还原损伤的蛋白质，而不会导致代谢或信号传递所需的氧化还原网络的异常变化。在此背景下，重要的是要了解(I)NRF2介导的氧化还原信号或(Ii)自噬介导的抗氧化/还原途径在细胞发病机制中如何感知细胞损伤。最近的研究表明，蛋白质硫醇的修饰在调节Keap1-NRF2和自噬途径中起着重要的作用。在这里，我们讨论的证据表明，Keap1-NRF2途径和自噬协同作用，以对抗蛋白毒性的有害影响。这些发现的讨论将特别强调它们对心血管疾病和神经退行性变的影响。
Maintaining cellular redox status to allow cell signaling to occur requires modulation of both the controlled production of oxidants and the thiol reducing networks to allow specific regulatory post-translational modification of protein thiols. The oxidative stress hypothesis captures the concept that over production of oxidants can be proteotoxic but failed to predict the recent findings that hyper-activation of the KEAP1-NRF2 system also leads to proteotoxicity. Further, sustained activation of thiol redox networks by KEAP1-NRF2 induces a reductive stress, by decreasing the lifetime of necessary oxidative post-translational modifications required for normal metabolism or cell signaling. In this context it is now becoming clear why antioxidants or hyper-activation of antioxidant pathways with electrophilic therapeutics can be deleterious. Further it suggests that the autophagy-lysosomal pathway is particularly important in protecting the cell against redox stress-induced proteotoxicity, since it can degrade redox damaged proteins without causing aberrant changes to the redox network needed for metabolism or signaling. In this context, it is important to understand (i) how NRF2-mediated redox signaling or (ii) the autophagy-mediated anti-oxidant/reductant pathways sense cellular damage in the context of cellular pathogenesis. Recent studies indicate that the modification of protein thiols plays an important role in the regulation of both the KEAP1-NRF2 and autophagy pathways. Here we discuss evidence demonstrating that the KEAP1-NRF2 pathway and autophagy act in concert to combat the deleterious effects of proteotoxicity. These findings will be discussed with a special emphasis on their impact on cardiovascular disease and neurodegeneration.