Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis.
Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis.
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DOI：
10.1016/j.cell.2009.01.033
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发表时间：
2009-03-20
期刊：
影响因子：
64.5
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Lin YY;Lu JY;Zhang J;Walter W;Dang W;Wan J;Tao SC;Qian J;Zhao Y;Boeke JD;Berger SL;Zhu H
在后生动物中，组蛋白乙酰转移酶(HATS)和组蛋白脱乙酰酶(HDACs)通过非组蛋白底物发挥许多重要作用，但在酿酒酵母中，只有与染色质相关的非组蛋白底物是已知的。利用酵母蛋白质组芯片，我们鉴定和验证了H4(NuA4)复合体必需核小体乙酰转移酶的许多非染色质底物。其中，用串联质谱法测定了磷酸烯醇式丙酮酸羧酸激酶(Pck 1p)的乙酰化位点(Lys 19和514)。Lys 514上的乙酰化对于酵母酶活性和酵母细胞在非发酵碳源上生长的能力是至关重要的。Pck 1p活性的丧失阻碍了水分饥饿引起的酵母时间寿命的延长。在人肝细胞癌(HepG2)细胞中，人Pck 1乙酰化和葡萄糖的产生依赖于人ESA1的同源物Tip60。我们的结果证明了NuA4复合体通过乙酰化一种关键的代谢酶来调节葡萄糖代谢和寿命的新功能。
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 (Lys 19 and 514) of phosphoenolpyruvate carboxykinase (Pck1p) were determined by tandem mass spectrometry. Acetylation at Lys 514 was crucial for enzymatic activity and the ability of yeast cells to grow on non-fermentable carbon sources. 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 was dependent on TIP60, the human homolog of ESA1. Our results demonstrate a novel regulatory function for the NuA4 complex in glucose metabolism and life span by acetylating a critical metabolic enzyme.
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