PLoS ONE (Jan 2010)

Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2α/ATF4 pathway.

  • Valérie Carraro,
  • Anne-Catherine Maurin,
  • Sarah Lambert-Langlais,
  • Julien Averous,
  • Cédric Chaveroux,
  • Laurent Parry,
  • Céline Jousse,
  • Daima Ord,
  • Tõnis Ord,
  • Pierre Fafournoux,
  • Alain Bruhat

DOI
https://doi.org/10.1371/journal.pone.0015716
Journal volume & issue
Vol. 5, no. 12
p. e15716

Abstract

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In mammals, plasma amino acid concentrations are markedly affected by dietary or pathological conditions. It has been well established that amino acids are involved in the control of gene expression. Up to now, all the information concerning the molecular mechanisms involved in the regulation of gene transcription by amino acid availability has been obtained in cultured cell lines. The present study aims to investigate the mechanisms involved in transcriptional activation of the TRB3 gene following amino acid limitation in mice liver. The results show that TRB3 is up-regulated in the liver of mice fed a leucine-deficient diet and that this induction is quickly reversible. Using transient transfection and chromatin immunoprecipitation approaches in hepatoma cells, we report the characterization of a functional Amino Acid Response Element (AARE) in the TRB3 promoter and the binding of ATF4, ATF2 and C/EBPβ to this AARE sequence. We also provide evidence that only the binding of ATF4 to the AARE plays a crucial role in the amino acid-regulated transcription of TRB3. In mouse liver, we demonstrate that the GCN2/eIF2α/ATF4 pathway is essential for the induction of the TRB3 gene transcription in response to a leucine-deficient diet. Therefore, this work establishes for the first time that the molecular mechanisms involved in the regulation of gene transcription by amino acid availability are functional in mouse liver.