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24, chemin de Borde Rouge –Auzeville – CS52627
31326 Castanet Tolosan CEDEX - France

Dernière mise à jour : Mai 2018

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Human Nutrition Unit

Zone de texte éditable et éditée et rééditée

Alain Bruhat

Alain Bruhat’s profile

Field of Research

Feeding an amino acid-imbalanced diet is a frequent nutritional situation for omnivorous animals living in the wild. This is particularly the case when only a single plant protein source is available, which is most likely partially deficient for one essential amino acid (EAA). Eating a diet partially lacking an EAA results in a decrease in the concentration of the limiting AA in the plasma of the animal that will consequently regulate several physiological functions such as autophagy, food intake…

In addition to nutritional insults, pathological states characterized by a negative nitrogen balance and significant loss of lean body mass, such as cachexia and wasting syndromes can also lead to marked changes in the profiles of free AA in plasma that may affect the activity of the AA-regulated pathways. These pathological states include various forms of trauma (thermal burn, sepsis, fever...) as well as several diseases (chronic renal, cardiac, hepatic and pulmonary diseases, AIDS, cancer…).

These observations led us to decipher the molecular mechanisms involved in the control of physiological functions by amino acids availability.

To answer these questions we address three objectives:

1- Identify the signalling pathways involved in the regulation of gene expression in response to AA starvation in mammals.

2- Identify the physiological functions regulated by the Amino Acid regulated pathway.

3- Identify the role of signalling pathways regulated by amino acids availability in complex nutritional and/or pathological situations.

            Finally, we valorised our basic molecular studies on amino acid control of gene transcription by optimizing a nutritionally inducible system for controlling a therapeutic transgene expression in gene therapy strategies.


Research Activity

My research projects aim:

(1) to characterize the transcriptional mechanisms involved in adaptation to EAA deprivation in mammalian cells. We were pioneer in the characterization of the first Amino Acid Response Element (AARE) sequence (Bruhat et al, Mol Cell Biol 2000)

(2) to study these mechanisms at the level of the whole animal in several nutritional and pathophysiological situations.

- Study the role of the eIF2α/ATF4 signaling pathway in the transcriptional regulation of genes involved in apoptotic and autophagic processes: Demonstration that (i) the GCN2-eIF2α-ATF4 pathway regulates the transcription of many genes involved in the maintenance of the autophagic process and (ii) the CHOP transcription factor plays a key role both in the control of autophagy and in cell death in response to EAA deficiency. (B'chir et al, Nucleic Acids Res 2013) (B'chir et al, Cell Signal. 2014)

- Study the role of the eIF2α/ATF4 signaling pathway at the level of the whole animal according to nutritional and pathophysiological situations: (i) Validation of the GCN2-eIF2α-ATF4 pathway functionality in mice; (ii) Demonstration that the GCN2 kinase plays a key role in the induction of TRB3 transcription in mice liver following the consumption of an EAA-deficient diet. (Carraro et al, PLoS One 2010).

- Generation of a novel luciferase mouse line to visualize the spatiotemporal activity of the eIF2/ATF4 pathway: Profiling the eIF2α-ATF4 pathway induction pattern at the tissue and cellular levels. This reporter mouse model represents an important tool for investigating the role of the eIF2α/ATF4 pathway in physiology and diseases (catabolic states, hepatic fibrosis, obesity, diabetes, cancer ...) (Chaveroux et al, Science Signal 2015).

- Development of an inducible gene expression system by nutritional manipulation for gene therapy applications: The system includes an artificial promoter inducible by a deficiency in EAA and an EAA-deficient diet through the GCN2-eIF2α-ATF4 pathway. This system highlights a new concept in the field of gene therapy, that synthetic diets can enable a tight and robust temporal control of therapeutic transgene expression. (Chaveroux et al, Nat Biotechnol 2016)

7 Major publications

Chaveroux C, Bruhat A, Carraro V, Jousse C, Averous J, Maurin AC, Parry L, Mesclon F, Muranishi Y, Cordelier P, Meulle A, Baril P, Do Thi A, Ravassard P, Mallet J, Fafournoux P. Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids. Nat Biotechnol. 2016 Jul;34(7):746-51.

Chaveroux C, Carraro V, Canaple L, Averous J, Maurin AC, Jousse C, Muranishi Y, Parry L, Mesclon F, Gatti E, Mallet J, Ravassard P, Pierre P, Fafournoux P, Bruhat A. In vivo imaging of the spatiotemporal activity of the eIF2α-ATF4 signaling pathway: Insights into stress and related disorders. Science Signal. 2015 Apr 28;8(374):rs5.

B'chir W, Chaveroux C, Carraro V, Averous J, Maurin AC, Jousse C, Muranishi Y, Parry L, Fafournoux P, Bruhat A. Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation. Cell Signal. 2014 Jul;26(7):1385-91.

B'chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G, Fafournoux P, Bruhat A. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013 Sep;41(16):7683-99.

Carraro V, Maurin AC, Lambert-Langlais S, Averous J, Chaveroux C, Parry L, Jousse C, Ord D, Ord T, Fafournoux P, Bruhat A. Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2α/ATF4 pathway. PLoS One. 2010 Dec 21;5(12):e15716.

Chérasse Y, Maurin AC, Chaveroux C, Jousse C, Carraro V, Parry L, Deval C, Chambon C, Fafournoux P, Bruhat A. The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP. Nucleic Acids Res. 2007;35(17):5954-65.

Bruhat A, Jousse C, Carraro V, Reimold AM, Ferrara M, Fafournoux P. Amino acids control mammalian gene transcription: activating transcription factor 2 is essential for the amino acid responsiveness of the CHOP promoter. Mol Cell Biol. 2000 Oct;20(19):7192-204.