Protein Acetylation Microarray Reveals that NuA4 Controls Key Metabolic Target Regulating Gluconeogenesis

Yu yi Lin; Jin ying Lu; Junmei Zhang; Wendy Walter; Weiwei Dang; Jun Wan; Sheng Ce Tao; Jiang Qian; Yingming Zhao; Jef D. Boeke; Shelley L. Berger; Heng Zhu

doi:10.1016/j.cell.2009.01.033

Protein Acetylation Microarray Reveals that NuA4 Controls Key Metabolic Target Regulating Gluconeogenesis

Yu yi Lin, Jin ying Lu, Junmei Zhang, Wendy Walter, Weiwei Dang, Jun Wan, Sheng Ce Tao, Jiang Qian, Yingming Zhao, Jef D. Boeke, Shelley L. Berger, Heng Zhu

School of Medicine

Research output: Contribution to journal › Article › peer-review

231 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1073-1084
Number of pages	12
Journal	Cell
Volume	136
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2009.01.033
State	Published - Mar 20 2009

Keywords

CELLBIO
HUMDISEASE
PROTEINS

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2009.01.033

Cite this

@article{d4d2a26ca45344d0b7fb86c2a2c7f0a5,

title = "Protein Acetylation Microarray Reveals that NuA4 Controls Key Metabolic Target Regulating Gluconeogenesis",

abstract = "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.",

keywords = "CELLBIO, HUMDISEASE, PROTEINS",

author = "Lin, {Yu yi} and Lu, {Jin ying} and Junmei Zhang and Wendy Walter and Weiwei Dang and Jun Wan and Tao, {Sheng Ce} and Jiang Qian and Yingming Zhao and Boeke, {Jef D.} and Berger, {Shelley L.} and Heng Zhu",

note = "Funding Information: We thank E.M. Cooper, L. Dai, A. Norris, and K.A. O'Donnell for gifts of reagents; J. Liu, J.T. Stivers, H. Takahashi, S. Taverna, J. Zhang, and members of the Zhu and Boeke labs for valuable discussions throughout the course of the work. This work was supported in part by National Institutes of Health Roadmap Grant U54 RR 020839, “Technology Center for Networks and Pathways” (to J.D.B., S.L.B., and H.Z.); the Keck Foundation (H.Z.); and National Institutes of Health Grants R01CA126832 (to Y.Z.) and R01EY017589 (to J.Q.). ",

year = "2009",

month = mar,

day = "20",

doi = "10.1016/j.cell.2009.01.033",

language = "English (US)",

volume = "136",

pages = "1073--1084",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Protein Acetylation Microarray Reveals that NuA4 Controls Key Metabolic Target Regulating Gluconeogenesis

AU - Lin, Yu yi

AU - Lu, Jin ying

AU - Zhang, Junmei

AU - Walter, Wendy

AU - Dang, Weiwei

AU - Wan, Jun

AU - Tao, Sheng Ce

AU - Qian, Jiang

AU - Zhao, Yingming

AU - Boeke, Jef D.

AU - Berger, Shelley L.

AU - Zhu, Heng

N1 - Funding Information: We thank E.M. Cooper, L. Dai, A. Norris, and K.A. O'Donnell for gifts of reagents; J. Liu, J.T. Stivers, H. Takahashi, S. Taverna, J. Zhang, and members of the Zhu and Boeke labs for valuable discussions throughout the course of the work. This work was supported in part by National Institutes of Health Roadmap Grant U54 RR 020839, “Technology Center for Networks and Pathways” (to J.D.B., S.L.B., and H.Z.); the Keck Foundation (H.Z.); and National Institutes of Health Grants R01CA126832 (to Y.Z.) and R01EY017589 (to J.Q.).

PY - 2009/3/20

Y1 - 2009/3/20

N2 - 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.

AB - 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.

KW - CELLBIO

KW - HUMDISEASE

KW - PROTEINS

UR - http://www.scopus.com/inward/record.url?scp=62149143727&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=62149143727&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2009.01.033

DO - 10.1016/j.cell.2009.01.033

M3 - Article

C2 - 19303850

AN - SCOPUS:62149143727

SN - 0092-8674

VL - 136

SP - 1073

EP - 1084

JO - Cell

JF - Cell

IS - 6

ER -

Protein Acetylation Microarray Reveals that NuA4 Controls Key Metabolic Target Regulating Gluconeogenesis

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this