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Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis.

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) conduct many critical functions through nonhistone substrates in metazoans, but only chromatin-associated nonhistone substrates are known in Saccharomyces cerevisiae. Using yeast proteome microarrays, we identified and validated many nonchromatin substrates of the essential nucleosome acetyltransferase of H4 (NuA4) complex. Among these, acetylation sites (Lys19 and 514) of phosphoenolpyruvate carboxykinase (Pck1p) were determined by tandem mass spectrometry. Acetylation at Lys514 was crucial for enzymatic activity and the ability of yeast cells to grow on nonfermentable carbon sources. Furthermore, Sir2p deacetylated Pck1p both in vitro and in vivo. Loss of Pck1p activity blocked the extension of yeast chronological life span caused by water starvation. In human hepatocellular carcinoma (HepG2) cells, human Pck1 acetylation and glucose production were dependent on TIP60, the human homolog of ESA1. Our findings demonstrate a regulatory function for the NuA4 complex in glucose metabolism and life span by acetylating a critical metabolic enzyme.

Pubmed ID: 19303850


  • Lin YY
  • Lu JY
  • Zhang J
  • Walter W
  • Dang W
  • Wan J
  • Tao SC
  • Qian J
  • Zhao Y
  • Boeke JD
  • Berger SL
  • Zhu H



Publication Data

March 20, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA126832
  • Agency: NCI NIH HHS, Id: R01 CA126832-02
  • Agency: NEI NIH HHS, Id: R01 EY017589
  • Agency: NEI NIH HHS, Id: R01 EY017589-02
  • Agency: NCI NIH HHS, Id: R01CA126832
  • Agency: NEI NIH HHS, Id: R01EY017589
  • Agency: NCRR NIH HHS, Id: U54 RR 020839
  • Agency: NCRR NIH HHS, Id: U54 RR020839
  • Agency: NCRR NIH HHS, Id: U54 RR020839-056887
  • Agency: NCRR NIH HHS, Id: U54 RR020839-056892
  • Agency: NCRR NIH HHS, Id: U54 RR020839-05S1

Mesh Terms

  • Acetylation
  • Gene Knockdown Techniques
  • Gluconeogenesis
  • Glucose
  • Histone Acetyltransferases
  • Histone Deacetylases
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Protein Array Analysis
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sirtuins
  • Water