Tyr Phosphorylation of PDP1 Toggles Recruitment between ACAT1 and SIRT3 to Regulate the Pyruvate Dehydrogenase Complex

被引：304

作者：

Fan, Jun ^{[1
]}

Shan, Changliang ^{[1
]}

Kang, Hee-Bum ^{[1
]}

Elf, Shannon ^{[1
]}

Xie, Jianxin ^{[3
]}

Tucker, Meghan ^{[3
]}

Gu, Ting-Lei ^{[3
]}

Aguiar, Mike ^{[3
]}

Lonning, Scott ^{[3
]}

Chen, Huaibin ^{[4
]}

Mohammadi, Moosa ^{[4
]}

Britton, Laura-Mae P. ^{[5
]}

Garcia, Benjamin A. ^{[5
]}

Aleckovic, Masa ^{[6
]}

Kang, Yibin ^{[6
]}

Kaluz, Stefan ^{[2
]}

Devi, Nara ^{[2
]}

Van Meir, Erwin G. ^{[1
,2
]}

Hitosugi, Taro ^{[1
]}

Seo, Jae Ho ^{[1
]}

Lonial, Sagar ^{[1
]}

Gaddh, Manila ^{[1
]}

Arellano, Martha ^{[1
]}

Khoury, Hanna J. ^{[1
]}

Khuri, Fadlo R. ^{[1
]}

Boggon, Titus J. ^{[7
]}

Kang, Sumin ^{[1
]}

Chen, Jing ^{[1
]}

机构：

[1] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Neurosurg, Winship Canc Inst Emory, Atlanta, GA 30322 USA

[3] Cell Signaling Technol Inc CST, Danvers, MA 01923 USA

[4] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA

[5] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

[6] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA

[7] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

来源：

MOLECULAR CELL | 2014年 / 53卷 / 04期

关键词：

CANCER-CELL METABOLISM; LYSINE ACETYLATION; GROWTH-FACTOR; TUMOR-GROWTH; PROTEIN; KINASE; HYPOXIA; TARGETS; ADAPTATION; SUPPRESSOR;

D O I：

10.1016/j.molcel.2013.12.026

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis 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 epidermal growth factor (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 in promoting 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 posttranslational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect.

引用

页码：534 / 548

页数：15

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