1. HIF-independent role of prolyl hydroxylases in the cellular response to amino acids.
- Author
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Durán RV, MacKenzie ED, Boulahbel H, Frezza C, Heiserich L, Tardito S, Bussolati O, Rocha S, Hall MN, and Gottlieb E
- Subjects
- Animals, Cell Line, Enzyme Activation, Humans, Ketoglutaric Acids metabolism, Mechanistic Target of Rapamycin Complex 1, Mice, Models, Biological, Multiprotein Complexes antagonists & inhibitors, Multiprotein Complexes metabolism, Procollagen-Proline Dioxygenase antagonists & inhibitors, TOR Serine-Threonine Kinases antagonists & inhibitors, TOR Serine-Threonine Kinases metabolism, Amino Acids metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Procollagen-Proline Dioxygenase metabolism
- Abstract
Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are α-ketoglutarate (αKG)-dependent dioxygenases that function as cellular oxygen sensors. However, PHD activity also depends on factors other than oxygen, especially αKG, a key metabolic compound closely linked to amino-acid metabolism. We examined the connection between amino-acid availability and PHD activity. We found that amino-acid starvation leads to αKG depletion and to PHD inactivation but not to HIF stabilization. Furthermore, pharmacologic or genetic inhibition of PHDs induced autophagy and prevented mammalian target of rapamycin complex 1 (mTORC1) activation by amino acids in a HIF-independent manner. Therefore, PHDs sense not only oxygen but also respond to amino acids, constituting a broad intracellular nutrient-sensing network.
- Published
- 2013
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