Journal
MOLECULAR CELL
Volume 53, Issue 4, Pages 534-548Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2013.12.026
Keywords
-
Categories
Funding
- NIH [CA140515, CA116804]
- Pharmacological Sciences Training [T32 GM008602]
- DoD [W81XWH-12-1-0217]
- Samuel V Foundations
- Waxman V Foundations
- Max Cure V Foundations
- Hematology Tissue Bank of the Emory University School of Medicine
- Georgia Cancer Coalition
- Cell Signaling Technology, Inc.
- ARCS Foundation Scholar
- Georgia Cancer Coalition Distinguished Cancer Scholars
- Robbins Scholar
- American Cancer Society Basic Research Scholars
- Scholar of the Leukemia and Lymphoma Society
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available