Abstract
Activation of autophagy and elevation of glutamine synthesis represent key adaptations to maintain amino acid balance during starvation. In this study, we investigate the role of autophagy and glutamine on the regulation of mTORC1, a critical kinase that regulates cell growth and proliferation. We report that supplementation of glutamine alone is sufficient to restore mTORC1 activity during prolonged amino acid starvation. Inhibition of autophagy abolishes the restorative effect of glutamine, suggesting that reactivation of mTORC1 is autophagy-dependent. Inhibition of glutaminolysis or transamination impairs glutamine-mediated mTORC1 reactivation, suggesting glutamine reactivates mTORC1 specifically through its conversion to glutamate and restoration of non-essential amino acid pool. Despite a persistent drop in essential amino acid pool during amino acid starvation, crosstalk between glutamine and autophagy is sufficient to restore insulin sensitivity of mTORC1. Thus, glutamine metabolism and autophagy constitute a specific metabolic program which restores mTORC1 activity during amino acid starvation.
Highlights
Activation of autophagy and elevation of glutamine synthesis represent key adaptations to maintain amino acid balance during starvation
In the absence of glutamine, amino acid starvation led to a progressive loss in the phosphorylation levels of 4E (eIF4E)-binding protein-1 (4EBP1) (T37/46), Unc51-like kinase 1 (ULK1) (S757), and p70S6K (T389), direct downstream targets of Mechanistic target of rapamycin complex 1 (mTORC1) (Fig. 1a)
Glutamine induced a restoration of mTORC1 signaling in the later phase of amino acid starvation, as shown by the recovery of p-4EBP1 (T37/46), p-ULK1 (S757) and p-p70S6K (T389) (Fig. 1a)
Summary
Activation of autophagy and elevation of glutamine synthesis represent key adaptations to maintain amino acid balance during starvation. We investigate the role of autophagy and glutamine on the regulation of mTORC1, a critical kinase that regulates cell growth and proliferation. We report that supplementation of glutamine alone is sufficient to restore mTORC1 activity during prolonged amino acid starvation. Despite a persistent drop in essential amino acid pool during amino acid starvation, crosstalk between glutamine and autophagy is sufficient to restore insulin sensitivity of mTORC1. Glutamine metabolism and autophagy constitute a specific metabolic program which restores mTORC1 activity during amino acid starvation. In response to amino acids and growth factor activation, mTORC1 phosphorylates eukaryotic translation initiation factor 4E (eIF4E)-binding protein-1. In response to autophagy-inducing signals such as amino acid starvation, ULK1 forms a complex with multiple proteins including ATG13 to initiate autophagy. Regulation of protein translation and autophagy by mTORC1 prevents futile cycles of protein synthesis and catabolism
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