title: Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1.
abstract: Phosphoglycerate kinase 1 (PGK1) catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. PGK1 plays a key role in coordinating glycolytic energy production with one-carbon metabolism, serine biosynthesis, and cellular redox regulation. Here, we report that PGK1 is acetylated at lysine 220 (K220), which inhibits PGK1 activity by disrupting the binding with its substrate, ADP. We have identified KAT9 and HDAC3 as the potential acetyltransferase and deacetylase, respectively, for PGK1. Insulin promotes K220 deacetylation to stimulate PGK1 activity. We show that the PI3K/AKT/mTOR pathway regulates HDAC3 S424 phosphorylation, which promotes HDAC3-PGK1 interaction and PGK1 K220 deacetylation. Our study uncovers a previously unknown mechanism for the insulin and mTOR pathway in regulation of glycolytic ATP production and cellular redox potential via HDAC3-mediated PGK1 deacetylation.
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Synthetic Biology, Bioinformatics Center and Laboratory of Systems Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Xiufei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Huaipeng
authors.initials: H
authors.lastname: Lin
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory of Synthetic Biology, Bioinformatics Center and Laboratory of Systems Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China; Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China; Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000107:Acetylation; D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D050260:Carbohydrate Metabolism; D004789:Enzyme Activation; D006019:Glycolysis; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010735:Phosphoglycerate Kinase / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D000244:Adenosine Diphosphate; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D009419:Nerve Tissue Proteins; D010735:Phosphoglycerate Kinase; D058570:TOR Serine-Threonine Kinases; D000099186:Histone Deacetylase 3; C538729:ELP3 protein, human; C546842:MTOR protein, human; C577282:PGK1 protein, human