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

• Type of Material: Article
• Authors: Jun Fan, Emory University; Changliang Shan, Emory University; HeeBum Kang, Emory University; Shannon Elf, Emory University; Jianxin Xie, Cell Signaling Technology, Inc.; Meghan Tucker, Cell Signaling Technology, Inc.; Ting-Lei Gu, Cell Signaling Technology, Inc.; Mike Aguiar, Cell Signaling Technology, Inc.; Scott Lonning, Cell Signaling Technology, Inc.; Huaibin Chen, New York University; Moosa Mohammadi, New York University; Laura-Mae P. Britton, Princeton University; Benjamin A. Garcia, Princeton University; Masa Aleckovic, University of Pennsylvania; Yibin Kang, University of Pennsylvania; Stefan Kaluz, Emory University; Narra Devi, Emory University; Erwin Van Meir, Emory University; Taro Hitosugi, Emory University; Jae Ho Seo, Emory University; Sagar Lonial, Emory University; Manila Gaddh, Emory University; Martha Arellano, Emory University; H Jean Khoury, Emory University; Fadlo Khuri, Emory University; Titus J. Boggon, Yale University; Su Kang, Emory University; Jing Chen, Emory University
• Language: English
• Date: 2014-02-20
• Publisher: Elsevier (Cell Press)
• Publication Version: Final Published Version
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2013.12.026
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 53
• Issue: 4
• Start Page: 534
• End Page: 548
• Grant/Funding Information: This work was supported in part by NIH grants CA140515 (J.C.) and the Pharmacological Sciences Training Grant T32 GM008602 (S.E.), DoD grant W81XWH-12-1-0217 (J.C.), and the Hematology Tissue Bank of the Emory University School of Medicine and the Georgia Cancer Coalition (H.J.K.).
• Keywords: TARGETS; Science & Technology; KINASE; BIOCHEMISTRY & MOLECULAR BIOLOGY; TUMOR-GROWTH; ADAPTATION; PROTEIN; Life Sciences & Biomedicine; Cell Biology; CELL BIOLOGY; Biochemistry & Molecular Biology; CANCER-CELL METABOLISM; HYPOXIA; LYSINE ACETYLATION; GROWTH-FACTOR; SUPPRESSOR
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation ofpyruvate 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. © 2014 Elsevier Inc.