Oxidation of multiple MiT/TFE transcription factors links oxidative stress to transcriptional control of autophagy and lysosome biogenesis
Oxidation of multiple MiT/TFE transcription factors links oxidative stress to transcriptional control of autophagy and lysosome biogenesis
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多种 MiT/TFE 转录因子的氧化将氧化应激与自噬和溶酶体生物发生的转录控制联系起来。
DOI：
10.1080/15548627.2019.1704104
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发表时间：
2019-12-19
期刊：
影响因子：
13.3
通讯作者：
Ying, Zheng
中科院分区：
文献类型：
--
作者：
Wang, Hongfeng;Wang, Nana;Ying, Zheng
重要证据表明，活性氧（ROS）在生理和病理条件下均可诱导巨自噬/自噬。尽管ROS与自噬调节之间的关系已得到充分研究，但ROS影响自噬的基本机制以及这种调节的生物学作用仍未完全清楚。在本研究中，我们发现包括TFEB、TFE3和MITF在内的多个MiT - TFE转录因子（它们是自噬和溶酶体生物发生的主要调节因子）可在被ROS直接半胱氨酸氧化后被激活。氧化通过抑制这些MiT - TFE转录因子与RRAG GTP酶的结合，促进它们的核转位，进而导致自噬 - 溶酶体系统中的全局基因表达水平提高。我们的研究强调了MiT - TFE转录因子氧化在与ROS相关的自噬中的作用，并提供了一种新的机制，即MiT - TFE转录因子介导的自噬转录控制可能在应对氧化应激时调控细胞内稳态，而氧化应激是一种与包括神经退行性疾病和癌症在内的人类疾病密切相关的生物学过程。
Significant evidences indicate that reactive oxygen species (ROS) can induce macroautophagy/autophagy under both physiological and pathological conditions. Although the relationship between ROS and autophagy regulation has been well studied, the basic mechanism by which ROS affects autophagy and the biological role of this regulation are still not fully understood. In the present study we show that multiple MiT-TFE transcription factors including TFEB, TFE3 and MITF, which are master regulators of autophagy and lysosomal biogenesis, can be activated upon direct cysteine oxidation by ROS. Oxidation promotes the nuclear translocation of these MiT-TFE transcription factors by inhibiting the association of them with RRAG GTPases, which in turn leads to enhanced global gene expression level in autophagy-lysosome system. Our study highlights the role of oxidation of MiT-TFE transcription factors in ROS-linked autophagy, and provides novel mechanism that MiT-TFE transcription factors-mediated transcriptional control of autophagy may govern cell homeostasis in response to oxidative stress, a biological process tightly linked to human diseases including neurodegenerative diseases and cancer.