title: AMPK-Dependent Phosphorylation of GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation.
abstract: Eukaryotes initiate autophagy to cope with the lack of external nutrients, which requires the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase Sirtuin 1 (Sirt1). However, the mechanisms underlying the starvation-induced Sirt1 activation for autophagy initiation remain unclear. Here, we demonstrate that glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a conventional glycolytic enzyme, is a critical mediator of AMP-activated protein kinase (AMPK)-driven Sirt1 activation. Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. Preventing this shift of GAPDH abolishes Sirt1 activation and autophagy, while enhancing it, through overexpression of nuclear-localized GAPDH, increases Sirt1 activation and autophagy. GAPDH is thus a pivotal and central regulator of autophagy under glucose deficiency, undergoing AMPK-dependent phosphorylation and nuclear translocation to activate Sirt1 deacetylase activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Danhong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Yusha
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Zhou
authors.affiliation: National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Peng
authors.affiliation: National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.affiliation: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lippincott-Schwartz
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: liuwei666@zju.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology; D005947:Glucose / Q000172:deficiency*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C112308:BRINP1 protein, human; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D012694:Serine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005947:Glucose