title: 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: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: C
authors: C
authors: D'Aniello
authors: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: A
authors: A
authors: Fico
authors: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: L
authors: L
authors: Casalino
authors: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: O
authors: O
authors: Guardiola
authors: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: G
authors: G
authors: Di Napoli
authors: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: F
authors: F
authors: Cermola
authors: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: D
authors: D
authors: De Cesare
authors: Integrated Microscopy, Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: R
authors: R
authors: Tatè
authors: Department of Biophysics, Biochemistry and General Pathology, Second University of Naples (SUN), Naples, Italy.
authors: G
authors: G
authors: Cobellis
authors: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: E J
authors: EJ
authors: Patriarca
authors: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
authors: G
authors: G
authors: Minchiotti
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D053595:Embryonic Stem Cells / Q000378:metabolism*; D025461:Feedback, Physiological; D051379:Mice; D011392:Proline / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: C081452:Atf4 protein, mouse; D051701:Activating Transcription Factor 4; D011392:Proline; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases