A novel autoregulatory loop between the Gcn2-Atf4 pathway and (L)-Proline [corrected] metabolism controls stem cell identity.

Abstract

Increasing evidence indicates that metabolism is implicated in the control of stem cell identity. Here, we demonstrate that embryonic stem cell (ESC) behaviour relies on a feedback loop that involves the non-essential amino acid L-Proline (L-Pro) in the modulation of the Gcn2-Eif2α-Atf4 amino acid starvation response (AAR) pathway that in turn regulates L-Pro biosynthesis. This regulatory loop generates a highly specific intrinsic shortage of L-Pro that restricts proliferation of tightly packed domed-like ESC colonies and safeguards ESC identity. Indeed, alleviation of this nutrient stress condition by exogenously provided L-Pro induces proliferation and modifies the ESC phenotypic and molecular identity towards that of mesenchymal-like, invasive pluripotent stem cells. Either pharmacological inhibition of the prolyl-tRNA synthetase by halofuginone or forced expression of Atf4 antagonises the effects of exogenous L-Pro. Our data provide unprecedented evidence that L-Pro metabolism and the nutrient stress response are functionally integrated to maintain ESC identity.

• Authors: C D'Aniello, A Fico, L Casalino, O Guardiola, G Di Napoli, F Cermola, D De Cesare, R Tatè, G Cobellis, E J Patriarca, G Minchiotti
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 22 Issue 7 Pg. 1094-105 (Jul 2015) ISSN: 1476-5403 [Electronic] England
• PMID: 25857264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Atf4 protein, mouse
• Activating Transcription Factor 4
• Proline
• Eif2ak4 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Activating Transcription Factor 4 (metabolism)
• Animals
• Embryonic Stem Cells (metabolism)
• Feedback, Physiological
• Mice
• Proline (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction
• Stress, Physiological