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

Cell Death Differ. 2015 Jul;22(7):1094-105. doi: 10.1038/cdd.2015.24. Epub 2015 Apr 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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