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Branched-Chain Aminotransferases Control TORC1 Signaling in Saccharomyces cerevisiae.

Publication ,  Journal Article
Kingsbury, JM; Sen, ND; Cardenas, ME
Published in: PLoS Genet
December 2015

The conserved target of rapamycin complex 1 (TORC1) integrates nutrient signals to orchestrate cell growth and proliferation. Leucine availability is conveyed to control TORC1 activity via the leu-tRNA synthetase/EGOC-GTPase module in yeast and mammals, but the mechanisms sensing leucine remain only partially understood. We show here that both leucine and its α-ketoacid metabolite, α-ketoisocaproate, effectively activate the yeast TORC1 kinase via both EGOC GTPase-dependent and -independent mechanisms. Leucine and α-ketoisocaproate are interconverted by ubiquitous branched-chain aminotransferases (BCAT), which in yeast are represented by the mitochondrial and cytosolic enzymes Bat1 and Bat2, respectively. BCAT yeast mutants exhibit severely compromised TORC1 activity, which is partially restored by expression of Bat1 active site mutants, implicating both catalytic and structural roles of BCATs in TORC1 control. We find that Bat1 interacts with branched-chain amino acid metabolic enzymes and, in a leucine-dependent fashion, with the tricarboxylic acid (TCA)-cycle enzyme aconitase. BCAT mutation perturbed TCA-cycle intermediate levels, consistent with a TCA-cycle block, and resulted in low ATP levels, activation of AMPK, and TORC1 inhibition. We propose the biosynthetic capacity of BCAT and its role in forming multicomplex metabolons connecting branched-chain amino acids and TCA-cycle metabolism governs TCA-cycle flux to activate TORC1 signaling. Because mammalian mitochondrial BCAT is known to form a supramolecular branched-chain α-keto acid dehydrogenase enzyme complex that links leucine metabolism to the TCA-cycle, these findings establish a precedent for understanding TORC1 signaling in mammals.

Duke Scholars

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

December 2015

Volume

11

Issue

12

Start / End Page

e1005714

Location

United States

Related Subject Headings

  • Transaminases
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Saccharomyces cerevisiae Proteins
  • Saccharomyces cerevisiae
  • Multiprotein Complexes
  • Mitochondrial Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • Leucine
  • Keto Acids
 

Citation

APA
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MLA
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Kingsbury, J. M., Sen, N. D., & Cardenas, M. E. (2015). Branched-Chain Aminotransferases Control TORC1 Signaling in Saccharomyces cerevisiae. PLoS Genet, 11(12), e1005714. https://doi.org/10.1371/journal.pgen.1005714
Kingsbury, Joanne M., Neelam D. Sen, and Maria E. Cardenas. “Branched-Chain Aminotransferases Control TORC1 Signaling in Saccharomyces cerevisiae.PLoS Genet 11, no. 12 (December 2015): e1005714. https://doi.org/10.1371/journal.pgen.1005714.
Kingsbury JM, Sen ND, Cardenas ME. Branched-Chain Aminotransferases Control TORC1 Signaling in Saccharomyces cerevisiae. PLoS Genet. 2015 Dec;11(12):e1005714.
Kingsbury, Joanne M., et al. “Branched-Chain Aminotransferases Control TORC1 Signaling in Saccharomyces cerevisiae.PLoS Genet, vol. 11, no. 12, Dec. 2015, p. e1005714. Pubmed, doi:10.1371/journal.pgen.1005714.
Kingsbury JM, Sen ND, Cardenas ME. Branched-Chain Aminotransferases Control TORC1 Signaling in Saccharomyces cerevisiae. PLoS Genet. 2015 Dec;11(12):e1005714.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

December 2015

Volume

11

Issue

12

Start / End Page

e1005714

Location

United States

Related Subject Headings

  • Transaminases
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Saccharomyces cerevisiae Proteins
  • Saccharomyces cerevisiae
  • Multiprotein Complexes
  • Mitochondrial Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • Leucine
  • Keto Acids