HIF-independent role of prolyl hydroxylases in the cellular response to amino acids

Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are a-ketoglutarate (aKG)-dependent dioxygenases that function as cellular oxygen sensors. However, PHD activity also depends on factors other than oxygen, especially aKG, 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 aKG 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.Oncogene advance online publication, 22 October 2012; doi:10.1038/onc.2012.465.