Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.

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.