Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Redox Homeostasis Group, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
EMBO J. 2021 Feb 1;40(3):e105793. doi: 10.15252/embj.2020105793. Epub 2020 Dec 14.
Mammalian TFEB and TFE3, as well as their ortholog in Caenorhabditis elegans HLH-30, play an important role in mediating cellular response to a variety of stress conditions, including nutrient deprivation, oxidative stress, and pathogen infection. In this study, we identify a novel mechanism of TFEB/HLH-30 regulation through a cysteine-mediated redox switch. Under stress conditions, TFEB-C212 undergoes oxidation, allowing the formation of intermolecular disulfide bonds that result in TFEB oligomerization. TFEB oligomers display increased resistance to mTORC1-mediated inactivation and are more stable under prolonged stress conditions. Mutation of the only cysteine residue present in HLH-30 (C284) significantly reduced its activity, resulting in developmental defects and increased pathogen susceptibility in worms. Therefore, cysteine oxidation represents a new type of TFEB post-translational modification that functions as a molecular switch to link changes in redox balance with expression of TFEB/HLH-30 target genes.
哺乳动物 TFEB 和 TFE3 及其在秀丽隐杆线虫中的同源物 HLH-30 在介导细胞对各种应激条件（包括营养缺乏、氧化应激和病原体感染）的反应中发挥着重要作用。在这项研究中，我们通过半胱氨酸介导的氧化还原开关发现了 TFEB/HLH-30 调节的一种新机制。在应激条件下，TFEB-C212 发生氧化，允许形成导致 TFEB 寡聚化的分子间二硫键。TFEB 寡聚体对 mTORC1 介导的失活表现出更高的抗性，并且在延长的应激条件下更稳定。存在于 HLH-30 中的唯一半胱氨酸残基（C284）的突变显著降低了其活性，导致线虫发育缺陷和病原体易感性增加。因此，半胱氨酸氧化代表了一种新的 TFEB 翻译后修饰类型，作为一种分子开关，将氧化还原平衡的变化与 TFEB/HLH-30 靶基因的表达联系起来。
