Dynamic investigation of hypoxia- induced L- lactylation

• 成果类型: Article
• 署名作者: Gao, Jinjun; Liu, Ruilong; Huang, Kevin; Li, Ziyuan; Sheng, Xinlei; Chakraborty, Kasturi; Han, Chang; Zhang, Di; Becker, Lev; Zhao, Yingming
• 署名单位: University of Chicago; Cornell University; University of Wisconsin System; University of Wisconsin Madison; Peking University; Peking University; Peking University Shenzhen Graduate School (PKU Shenzhen); Peking University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14087
• DOI: 10.1073/pnas.2404899122
• 发表日期: 2025-03-11
• 关键词: inhibitor; lactate; methylglyoxal; dehydrogenase; metabolism; expression; mechanism

摘要

The recently identified histone modification lysine lactylation can be stimulated by L- lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L- enantiomer of lactate (KL- la), two isomeric modifications, their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood. In this study, we demonstrate that intracellular KL- la, but not KD- la or Kce, is up- regulated in response to hypoxia. Depletion of glyoxalase enzymes, GLO1 and GLO2, had minflux to L- lactate under hypoxic conditions by knocking out lactate dehydrogenase A/B completely abolished the induction of KL- la but increased KD- la and Kce. We further observed a correlation between the level of KL- la and hypoxia- inducible factor 1 alpha (HIF- 1 alpha) expression under hypoxic conditions and when small molecules were used to stabilize HIF- 1 alpha in the normoxia condition. Our result demonstrated that there is we quantified 66 KL- la sites that were up- regulated by hypoxia and demonstrated that adaptation of tumor cells.