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Last update: May 2021

Menu Logo Principal logo Université Clermont Auvergne & associés

Human Nutrition Unit

Zone de texte éditable et éditée et rééditée

Dr Julien Averous

Julien Averous' profile
AVEROUS-Julien

Field of research

            Amino acids exhibit two important characteristics. Firstly, in mammals, 9 amino acids, called indispensable amino acid, cannot be synthesized de novo. Secondly, there is no specific storage of amino acids analogous to glycogen for glucose or triglyceride of adipose tissue for lipids. Consequently, when necessary, an organism has to hydrolyse endogenous protein to produce free amino acids. This loss of protein will be at the expense of essential elements. At the cellular, amino acid availability regulates a number of signal transduction pathways that leads to activation of specific functions (transcription, autophagy, …) playing a key role in adaptation to nutrient stress. The GCN2 and the mTORC1 signaling pathways are well known to be regulated by amino acid availability, and to share common functions, in particular the control of protein synthesis. Despite recent significant progress in the understanding of the regulation of mTORC1 by amino acids, key aspects of this process remain unsolved. This topic is the centre of a particular attention, given the fundamental importance of mTORC1 in many physiological functions and in several pathologies. Contrary to mTORC1, the regulation of GCN2 activity by amino acid availability has been well characterized. It relies on the capacity of GCN2 to sense the increased level of uncharged tRNAs upon amino acid scarcity. It is only recently that, an increasing number of data from animal models or clinical studies reveal an important role of the GCN2 pathway in the regulation of physiological and pathological processes. Beyond the role of these two pathways, it has to be considered that other molecular mechanisms must be involved in the adaptation of cell to the modifications of amino acid availability. The comprehension of these different mechanisms is essential to better apprehend the impact of amino acids in physiological and pathological situations.

Research activities

Amino acid sensing and mTORC1/GCN2 interaction

We focused our investigation on the interaction between the GCN2/eIF2a pathway and the mTORC1 pathway. This pathway is well-known to be regulated by amino acid availability and is a master regulator of cell growth. Different studies suggest a role of GCN2 in the regulation of mTORC1. This project led us to complement the accepted model of mTORC1 regulation by amino acids and in particular by leucine. We demonstrated that leucine activates mTORC1 without causing any detectable modification of the lysosomal localization of mTOR. Moreover, leucine can promote mTORC1 signaling independently of the lysosomal localization of mTOR.

Identification of the molecular mechanisms involved in the adaptation of cancer cells to amino acid starvation

Tumor development is closely associated with deep changes in cellular metabolism. The uncontrolled division of cancer cells involves a major expansion of the tumor, which will result in an inadequate availability of nutrients, especially oxygen, glucose and amino acids. If this nutrient-deprived environment contributes to the formation of the necrotic area, it also exerts a pressure of selection on tumor cells. Due to their genetic instability, secondary mutations are likely to generate cells highly resistant to nutrient deficiencies able to survive and colonize the tumor ("Darwinian” selection). In this project we focus on the identification of the molecular mechanisms involved in the long-term adaptation to an amino acids deficiency. We chose an original approach that consists in generating cellular tools by functional genetics. It consists in exerting a very strong selection pressure on mouse embryonic fibroblasts by culturing them for several months in a medium containing very low level of amino acids. Even though most of the cells died, some of them survived and formed clones that we isolated and kept on a strong selective pressure.

Publications

Mesclon F, Lambert-Langlais S, Carraro V, Parry L, Hainault I, Jousse C, Maurin AC, Bruhat A, Fafournoux P, Averous J. Decreased ATF4 expression as a mechanism of acquired resistance to long-term amino acid limitation in cancer cells. Oncotarget. 2017 Apr 18;8(16):27440-27453.

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. Sci Signal. 2015 Apr 28;8(374)

Averous J, Lambert-Langlais S, Carraro V, Gourbeyre O, Parry L, B'Chir W, Muranishi Y, Jousse C, Bruhat A, Maurin AC, Proud CG, Fafournoux P. Requirement for lysosomal localization of mTOR for its activation differs between leucine and other amino acids. Cell Signal. 2014 Sep;26(9):1918-27.

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.

Averous J, Gabillard JC, Seiliez I, Dardevet D. Leucine limitation regulates myf5 and myoD expression and inhibits myoblast differentiation. Exp Cell Res. 2012 Feb 1;318(3):217-27.

Averous J, Lambert-Langlais S, Cherasse Y, Carraro V, Parry L, B'chir W, Jousse C, Maurin AC, Bruhat A, Fafournoux P. Amino acid deprivation regulates the stress-inducible gene p8 via the GCN2/ATF4 pathway. Biochem Biophys Res Commun. 2011 Sep 16;413(1):24-9.

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