Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex.
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.
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Jun
J
Fan
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Changliang
C
Shan
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Hee-Bum
HB
Kang
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Shannon
S
Elf
Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
Jianxin
J
Xie
Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
Meghan
M
Tucker
Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
Ting-Lei
TL
Gu
Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
Mike
M
Aguiar
Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
Scott
S
Lonning
Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Huaibin
H
Chen
Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Moosa
M
Mohammadi
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Laura-Mae P
LM
Britton
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Benjamin A
BA
Garcia
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Maša
M
Alečković
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Yibin
Y
Kang
Department of Neurosurgery, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Stefan
S
Kaluz
Department of Neurosurgery, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Narra
N
Devi
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurosurgery, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Erwin G
EG
Van Meir
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Taro
T
Hitosugi
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Jae Ho
JH
Seo
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Sagar
S
Lonial
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Manila
M
Gaddh
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Martha
M
Arellano
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Hanna J
HJ
Khoury
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Fadlo R
FR
Khuri
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Titus J
TJ
Boggon
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
Sumin
S
Kang
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu.
Jing
J
Chen
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000378:metabolism*; D056566:Sirtuin 3 / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry*
D014443:Tyrosine; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D008239:Lysine