Nuclear pyruvate kinase M2 complex serves as a transcriptional coactivator of arylhydrocarbon receptor.
Nuclear pyruvate kinase M2 complex serves as a transcriptional coactivator of arylhydrocarbon receptor.
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DOI：
10.1093/nar/gkv967
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发表时间：
2016-01-29
影响因子：
14.9
通讯作者：
Matsuda T
中科院分区：
文献类型：
--
作者：
Matsuda S;Adachi J;Ihara M;Tanuma N;Shima H;Kakizuka A;Ikura M;Ikura T;Matsuda T
丙酮酸激酶M2（PKM2）和丙酮酸脱氢酶复合物（PDC）调节乙酰辅酶A的产生，乙酰辅酶A在包括组蛋白乙酰化在内的多种酶促反应中充当乙酰供体。然而，组蛋白乙酰化所需的乙酰辅酶A以基因背景依赖性方式确保的机制尚不清楚。在这里，我们表明，PKM2，PDC的E2亚基和组蛋白乙酰转移酶p300构成一个复杂的染色质与芳烃受体（AhR），一个转录因子与异生物质代谢。所有这些因子都以AhR依赖性方式被募集到AhR靶基因的增强子中。PKM2有助于增强细胞色素P450 1A1（CYP1A1）的转录，这是一种AhR靶基因，在CYP1A1增强子处组蛋白H3的赖氨酸9处乙酰化。PKM2的定点突变表明，这种组蛋白乙酰化的增强需要该酶的丙酮酸激酶活性。此外，我们发现，PDC活动存在于细胞核中。基于这些发现，我们提出了一个本地乙酰辅酶A生产系统，其中PKM2和PDC本地供应乙酰辅酶A p300从丰富的PEP组蛋白乙酰化的基因增强子，我们的数据表明，PKM2敏感AhR介导的解毒活跃增殖细胞，如癌症和胎儿细胞。
Pyruvate kinase M2 (PKM2) and pyruvate dehydrogenase complex (PDC) regulate production of acetyl-CoA, which functions as an acetyl donor in diverse enzymatic reactions, including histone acetylation. However, the mechanism by which the acetyl-CoA required for histone acetylation is ensured in a gene context-dependent manner is not clear. Here we show that PKM2, the E2 subunit of PDC and histone acetyltransferase p300 constitute a complex on chromatin with arylhydrocarbon receptor (AhR), a transcription factor associated with xenobiotic metabolism. All of these factors are recruited to the enhancer of AhR-target genes, in an AhR-dependent manner. PKM2 contributes to enhancement of transcription of cytochrome P450 1A1 (CYP1A1), an AhR-target gene, acetylation at lysine 9 of histone H3 at the CYP1A1 enhancer. Site-directed mutagenesis of PKM2 indicates that this enhancement of histone acetylation requires the pyruvate kinase activity of the enzyme. Furthermore, we reveal that PDC activity is present in nuclei. Based on these findings, we propose a local acetyl-CoA production system in which PKM2 and PDC locally supply acetyl-CoA to p300 from abundant PEP for histone acetylation at the gene enhancer, and our data suggest that PKM2 sensitizes AhR-mediated detoxification in actively proliferating cells such as cancer and fetal cells.