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.

Abbreviations

Bafi A1: bafilomycin A₁; EBSS: Earle’s balanced salt solution; EGFP: enhanced green fluorescent protein; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; ROS: reactive oxygen species; RPS6KB/p70S6K: ribosomal protein S6 kinase B; TFEB: transcription factor EB; WT: wild type.

中文翻译：

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多个 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。

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 与自噬调控的关系已经得到很好的研究，但 ROS 影响自噬的基本机制以及该调控的生物学作用仍未完全了解。在本研究中，我们表明多种 MiT-TFE 转录因子，包括 TFEB、TFE3 和 MITF，它们是自噬和溶酶体生物发生的主要调节因子，可以在 ROS 直接氧化半胱氨酸时被激活。氧化通过抑制这些 MiT-TFE 转录因子与 RRAG GTPases 的结合来促进它们的核易位，这反过来导致自噬-溶酶体系统中全局基因表达水平的提高。

缩写

Bafi A1：巴弗洛霉素 A ₁；EBSS：厄尔平衡盐溶液；EGFP：增强型绿色荧光蛋白；GAPDH：3-磷酸甘油醛脱氢酶；MAP1LC3B/LC3B：微管相关蛋白 1 轻链 3 β；MTORC1：雷帕霉素激酶复合物 1 的机制靶点；ROS：活性氧；RPS6KB/p70S6K：核糖体蛋白 S6 激酶 B；TFEB：转录因子EB；WT：野生型。