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.

中文翻译：

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乳酰化稳定 TFEB 以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 活性中起着至关重要的作用。在这里，我们表明乳酸分子可以共价修饰 TFEB，导致其乳酸化和稳定化。在机械上，K91 位点的乳酰化阻止 TFEB 与 E3 泛素连接酶 WWP2 相互作用，从而抑制 TFEB 泛素化和蛋白酶体降解，导致 TFEB 活性和自噬通量增加。使用针对乳酸化 K91 的特异性抗体，在临床人胰腺癌样本中观察到增强的 TFEB 乳酸化。我们的结果表明，乳酰化是 TFEB 调节的一种新模式，并且 TFEB 的乳酰化可能与快速增殖细胞（如癌细胞）中的高水平自噬有关。