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

ABSTRACT: Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are ?-ketoglutarate (?KG)-dependent dioxygenases that function as cellular oxygen sensors. However, PHD activity also depends on factors other than oxygen, especially ?KG, 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 ?KG 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.

SUBMITTER: Duran RV 

PROVIDER: S-EPMC3787797 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other