title: Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth.
abstract: Most tumor cells take up more glucose than normal cells but metabolize glucose via glycolysis even in the presence of normal levels of oxygen, a phenomenon known as the Warburg effect. Tumor cells commonly express the embryonic M2 isoform of pyruvate kinase (PKM2) that may contribute to the metabolism shift from oxidative phosphorylation to aerobic glycolysis and tumorigenesis. Here we show that PKM2 is acetylated on lysine 305 and that this acetylation is stimulated by high glucose concentration. PKM2 K305 acetylation decreases PKM2 enzyme activity and promotes its lysosomal-dependent degradation via chaperone-mediated autophagy (CMA). Acetylation increases PKM2 interaction with HSC70, a chaperone for CMA, and association with lysosomes. Ectopic expression of an acetylation mimetic K305Q mutant accumulates glycolytic intermediates and promotes cell proliferation and tumor growth. These results reveal an acetylation regulation of pyruvate kinase and the link between lysine acetylation and CMA.
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University, Shanghai 200032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lv
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.forename: Ruiting
authors.initials: R
authors.lastname: Lin
authors.forename: Yajing
authors.initials: Y
authors.lastname: Chu
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Zha
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Zi
authors.initials: Z
authors.lastname: Li
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Yiran
authors.initials: Y
authors.lastname: Huang
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
mesh_terms: D000107:Acetylation; D000818:Animals; D001343:Autophagy; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005947:Glucose / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D005947:Glucose; D007527:Isoenzymes; D008239:Lysine; D018832:Molecular Chaperones; D011770:Pyruvate Kinase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor