Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth.
Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth.
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DOI：
10.1016/j.molcel.2011.04.025
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发表时间：
2011-06-24
期刊：
影响因子：
16
通讯作者：
Lei QY
中科院分区：
文献类型：
--
作者：
Lv L;Li D;Zhao D;Lin R;Chu Y;Zhang H;Zha Z;Liu Y;Li Z;Xu Y;Wang G;Huang Y;Xiong Y;Guan KL;Lei QY
大多数肿瘤细胞比正常细胞吸收更多的葡萄糖，但即使在正常水平的氧气存在下，也通过糖酵解代谢葡萄糖，这种现象称为瓦尔堡效应。肿瘤细胞通常表达丙酮酸激酶（PKM2）的胚胎M2亚型，这可能有助于代谢从氧化磷酸化转变为有氧糖酵解和肿瘤发生。在这里，我们表明，PKM2的赖氨酸305乙酰化，这种乙酰化是由高浓度的葡萄糖刺激。PKM2 K305乙酰化降低PKM2酶活性，并通过伴侣介导的自噬（CMA）促进其溶酶体依赖性降解。乙酰化增加了PKM2与HSC 70（CMA的伴侣）的相互作用以及与溶酶体的结合。乙酰化模拟物K305Q突变体的异位表达积累糖酵解中间产物并促进细胞增殖和肿瘤生长。这些结果揭示了丙酮酸激酶的乙酰化调节以及赖氨酸乙酰化与CMA之间的联系。
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.