2015
DOI: 10.1038/cdd.2015.24
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A novel autoregulatory loop between the Gcn2-Atf4 pathway and L-Proline 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 … Show more

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Cited by 55 publications
(92 citation statements)
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“…We thus performed a nuclear magnetic resonance (NMR)-based global metabolomic profiling of ESCs ± l -Pro and found strong differences in their metabolite content (Figure 3G and Table S4). In particular, PiCs showed increased levels of l -Pro and reduced levels of different amino acids ( l -Gln, l -Tyr, l -Gly, l -Ala l -Val, l -Leu, l -Ser) (Table S4), in line with our previous findings that l -Pro supplementation inactivates the amino acid stress response pathway in ESCs (D'Aniello et al., 2015). Remarkably, lactate levels significantly increased (Figures 3G, 3H, and S3F; Table S4) and PiCs were more susceptible to the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) compared with ESCs (Figures 3H, 3I, and S3G), suggesting a metabolic shift to glycolysis.…”
Section: Resultssupporting
confidence: 90%
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“…We thus performed a nuclear magnetic resonance (NMR)-based global metabolomic profiling of ESCs ± l -Pro and found strong differences in their metabolite content (Figure 3G and Table S4). In particular, PiCs showed increased levels of l -Pro and reduced levels of different amino acids ( l -Gln, l -Tyr, l -Gly, l -Ala l -Val, l -Leu, l -Ser) (Table S4), in line with our previous findings that l -Pro supplementation inactivates the amino acid stress response pathway in ESCs (D'Aniello et al., 2015). Remarkably, lactate levels significantly increased (Figures 3G, 3H, and S3F; Table S4) and PiCs were more susceptible to the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) compared with ESCs (Figures 3H, 3I, and S3G), suggesting a metabolic shift to glycolysis.…”
Section: Resultssupporting
confidence: 90%
“…Recent evidence from our laboratory demonstrates that ESCs suffer a highly specific intrinsic shortage of the nonessential amino acid l -Pro, which induces the amino acid stress response pathway (D'Aniello et al., 2015). Exogenously provided l -Pro alleviates this stress condition and converts round-shaped ESCs into flat-shaped pluripotent stem cells.…”
Section: Resultsmentioning
confidence: 99%
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“…A second pathway that was labeled equally strongly in both cell lines was proline biosynthesis. This pathway has recently been recognized as a critical pathway for cancer cells and embryonic stem cells (30,31) (Fig. 3F).…”
Section: Resultsmentioning
confidence: 99%
“…The uptake and metabolism of L-proline induces the differentiation of mouse embryonic stem (mES) cells into a later-stage pluripotent cell (early primitive ectoderm-like (EPL) cells) (Washington et al 2010, Tan et al 2011, and the regulation of intracellular L-proline concentrations has been linked to the maintenance of mES cells (D'Aniello et al 2015). mES and EPL cells differ in their differentiation kinetics, with EPL cells upregulating mesendoderm markers earlier than ES cells (Washington et al 2010).…”
Section: Amino Acid Utilization: Linking Metabolism To Epigeneticsmentioning
confidence: 99%