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

Jun Fan, Changliang Shan, Hee Bum Kang, Shannon Elf, Jianxin Xie, Meghan Tucker, Ting Lei Gu, Mike Aguiar, Scott Lonning, Huaibin Chen, Moosa Mohammadi, Laura Mae P. Britton, Benjamin A. Garcia, Maša Alečković, Yibin Kang, Stefan Kaluz, Narra Devi, Erwin G. VanMeir, Taro Hitosugi, Jae Ho SeoSagar Lonial, Manila Gaddh, Martha Arellano, Hanna J. Khoury, Fadlo R. Khuri, Titus J. Boggon, Sumin Kang, Jing Chen

Research output: Contribution to journalArticle

124 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)534-548
Number of pages15
JournalMolecular Cell
Volume53
Issue number4
DOIs
StatePublished - Feb 20 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Tyr Phosphorylation of PDP1 Toggles Recruitment between ACAT1 and SIRT3 to Regulate the Pyruvate Dehydrogenase Complex'. Together they form a unique fingerprint.

  • Cite this

    Fan, J., Shan, C., Kang, H. B., Elf, S., Xie, J., Tucker, M., Gu, T. L., Aguiar, M., Lonning, S., Chen, H., Mohammadi, M., Britton, L. M. P., Garcia, B. A., Alečković, M., Kang, Y., Kaluz, S., Devi, N., VanMeir, E. G., Hitosugi, T., ... Chen, J. (2014). Tyr Phosphorylation of PDP1 Toggles Recruitment between ACAT1 and SIRT3 to Regulate the Pyruvate Dehydrogenase Complex. Molecular Cell, 53(4), 534-548. https://doi.org/10.1016/j.molcel.2013.12.026