Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex.
Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex.
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DOI：
10.1016/j.molcel.2013.12.026
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发表时间：
2014-02-20
期刊：
影响因子：
16
通讯作者：
Chen, Jing
中科院分区：
文献类型：
--
作者：
Fan, Jun;Shan, Changliang;Kang, Hee-Bum;Elf, Shannon;Xie, Jianxin;Tucker, Meghan;Gu, Ting-Lei;Aguiar, Mike;Lonning, Scott;Chen, Huaibin;Mohammadi, Moosa;Britton, Laura-Mae P.;Garcia, Benjamin A.;Aleckovic, Masa;Kang, Yibin;Kaluz, Stefan;Devi, Nara;Van Meir, Erwin G.;Hitosugi, Taro;Seo, Jae Ho;Lonial, Sagar;Gaddh, Manila;Arellano, Martha;Khoury, Hanna J.;Khuri, Fadlo R.;Boggon, Titus J.;Kang, Sumin;Chen, Jing
线粒体丙酮酸脱氢酶复合体(PDC)对哺乳动物细胞的葡萄糖稳态起着至关重要的作用。目前对PDC调节的理解包括PDK抑制丙酮酸脱氢酶(PDH)的丝氨酸磷酸化，而PDH磷酸酶(PDP)去磷酸化PDH激活PDC。在此，我们报道了PDHA1和PDP1的赖氨酸乙酰化在EGF刺激的细胞和各种人类癌细胞中很常见。K321乙酰化通过招募PDK1抑制PDHA1，K202乙酰化通过解离其底物PDHA1抑制PDP1，两者都在促进癌细胞糖酵解和随后的肿瘤生长中起重要作用。此外，我们确定线粒体ACAT1和SIRT3分别是PDHA1和PDP1的上游乙酰转移酶和脱乙酰酶，而ACAT1的敲除抑制了肿瘤的生长。此外，PDP1的Y381磷酸化使SIRT3解离，并将ACAT1招募到PDC。在一起，分层的，不同的翻译后修饰协同作用，控制PDC的分子组成，并有助于Warburg效应。
Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homoeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here we report that lysine acetylation of PDHA1 and PDP1 is common in EGF-stimulated cells and diverse human cancer cells. K321 acetylation inhibits PDHA1 by recruiting PDK1 and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important to promote glycolysis in cancer cells and consequent tumor growth. Moreover, we identified mitochondrial ACAT1 and SIRT3 as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1, while knockdown of ACAT1 attenuates tumor growth. Furthermore, Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to PDC. Together, hierarchical, distinct post-translational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
代谢酶的乙酰化协调碳源利用和代谢通量
DOI：
10.1126/science.1179687
发表时间：
2010-02-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wang Q;Zhang Y;Yang C;Xiong H;Lin Y;Yao J;Li H;Xie L;Zhao W;Yao Y;Ning ZB;Zeng R;Xiong Y;Guan KL;Zhao S;Zhao GP
通讯作者：
Zhao GP
影响因子：
5.3
作者：
Boerner, JL;Demory, ML;Parsons, SJ
通讯作者：
Parsons, SJ
K433 乙酰化的促有丝分裂和致癌刺激可促进 PKM2 蛋白激酶活性和核定位。
影响因子：
16
作者：
Lv, Lei;Xu, Yan-Ping;Xiong, Yue
通讯作者：
Xiong, Yue
影响因子：
16
作者：
Hitosugi, Taro;Fan, Jun;Chung, Tae-Wook;Lythgoe, Katherine;Wang, Xu;Xie, Jianxin;Ge, Qingyuan;Gu, Ting-Lei;Polakiewicz, Roberto D.;Roesel, Johannes L.;Chen, Georgia Z.;Boggon, Titus J.;Lonial, Sagar;Fu, Haian;Khuri, Fadlo R.;Kang, Sumin;Chen, Jing
通讯作者：
Chen, Jing