Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.

IF 7.4 1区 生物学 Q1 CELL BIOLOGY Journal of Cell Biology Pub Date : 2024-11-04 Epub Date: 2024-08-28 DOI:10.1083/jcb.202308099
Yewei Huang, Gan Luo, Kesong Peng, Yue Song, Yusha Wang, Hongtao Zhang, Jin Li, Xiangmin Qiu, Maomao Pu, Xinchang Liu, Chao Peng, Dante Neculai, Qiming Sun, Tianhua Zhou, Pintong Huang, Wei Liu
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Abstract

The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells.

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乳化作用可稳定 TFEB,从而提高自噬和溶酶体活性。
转录因子 TFEB 是溶酶体生物发生和自噬的主要调节因子。越来越多的证据表明,翻译后修饰在调节 TFEB 活性方面发挥着至关重要的作用。在这里,我们发现乳酸分子可以对 TFEB 进行共价修饰,导致其乳化和稳定。从机理上讲,K91处的乳化可阻止TFEB与E3泛素连接酶WWP2相互作用,从而抑制TFEB的泛素化和蛋白酶体降解,导致TFEB活性和自噬通量增加。利用针对乳化 K91 的特异性抗体,在临床人类胰腺癌样本中观察到了增强的 TFEB 乳化作用。我们的研究结果表明,乳化是一种新型的 TFEB 调节模式,TFEB 的乳化可能与快速增殖细胞(如癌细胞)的高水平自噬有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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