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Int J Biol Sci 2022; 18(16):6210-6225. doi:10.7150/ijbs.75434 This issue Cite

Research Paper

Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages

Jizhuang Wang, Peilang Yang, Tianyi Yu, Min Gao, Dan Liu, Jie Zhang, Chenghao Lu, Xuelian Chen, Xiong Zhang^✉, Yan Liu^✉

Department of burn, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
*Co-corresponding authors.

✉ Corresponding authors: Dr. Yan Liu (E-mail: rjliuyancom) and Dr. Xiong Zhang (E-mail: xiongcom.cn). Address: Department of Burn, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Road, Shanghai, China 200025. More

Abstract

Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.

Keywords: Lactylation, PKM2, Glycolysis, Macrophage

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