2. Academic Validation
  3. Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity

Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity

  • J Cell Biol. 2024 Nov 4;223(11):e202308099. doi: 10.1083/jcb.202308099.
Yewei Huang # 1,  Gan Luo # 1,  Kesong Peng # 1,  Yue Song 2,  Yusha Wang 1,  Hongtao Zhang 1,  Jin Li 1,  Xiangmin Qiu 1,  Maomao Pu 1,  Xinchang Liu 1,  Chao Peng 3,  Dante Neculai 1,  Qiming Sun 1,  Tianhua Zhou 1,  Pintong Huang 2,  Wei Liu 1 2
Affiliations

Affiliations

  • 1 Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University , Yiwu, China.
  • 2 Department of Ultrasound Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 3 National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
  • # Contributed equally.
PMID: 39196068 DOI: 10.1083/jcb.202308099
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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