Sirtuin 1/sirtuin 3 are robust lysine delactylases and sirtuin 1-mediated delactylation regulates glycolysis
Runhua Du,
Yanmei Gao,
Cong Yan,
Xuelian Ren,
Shankang Qi,
Guobin Liu,
Xinlong Guo,
Xiaohan Song,
Hanmin Wang,
Jingxin Rao,
Yi Zang,
Mingyue Zheng,
Jia Li,
He Huang
Affiliations
Runhua Du
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Yanmei Gao
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
Cong Yan
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Xuelian Ren
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Shankang Qi
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Guobin Liu
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Xinlong Guo
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Xiaohan Song
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Hanmin Wang
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Jingxin Rao
State Key Laboratory of Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Yi Zang
Lingang Laboratory, Shanghai 201203, China
Mingyue Zheng
State Key Laboratory of Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Jia Li
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
He Huang
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Corresponding author
Summary: Lysine lactylation (Kla), an epigenetic mark triggered by lactate during glycolysis, including the Warburg effect, bridges metabolism and gene regulation. Enzymes such as p300 and HDAC1/3 have been pivotal in deciphering the regulatory dynamics of Kla, though questions about additional regulatory enzymes, their specific Kla substrates, and the underlying functional mechanisms persist. Here, we identify SIRT1 and SIRT3 as key ''erasers'' of Kla, shedding light on their selective regulation of both histone and non-histone proteins. Proteomic analysis in SIRT1/SIRT3 knockout HepG2 cells reveals distinct substrate specificities toward Kla, highlighting their unique roles in cellular signaling. Notably, we highlight the role of specific Kla modifications, such as those on the M2 splice isoform of pyruvate kinase (PKM2), in modulating metabolic pathways and cell proliferation, thereby expanding Kla’s recognized functions beyond epigenetics. Therefore, this study deepens our understanding of Kla’s functional mechanisms and broadens its biological significance.
