title: HIF-independent role of prolyl hydroxylases in the cellular response to amino acids.
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.
authors.affiliation: 1] Apoptosis and Tumour Metabolism Laboratory, Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow, UK [2] Biozentrum, University of Basel, Klingelbergstrasse 50/70, Basel, Switzerland.
authors.forename: R V
authors.initials: RV
authors.lastname: Durán
authors.forename: E D
authors.initials: ED
authors.lastname: MacKenzie
authors.forename: H
authors.initials: H
authors.lastname: Boulahbel
authors.forename: C
authors.initials: C
authors.lastname: Frezza
authors.forename: L
authors.initials: L
authors.lastname: Heiserich
authors.forename: S
authors.initials: S
authors.lastname: Tardito
authors.forename: O
authors.initials: O
authors.lastname: Bussolati
authors.forename: S
authors.initials: S
authors.lastname: Rocha
authors.forename: M N
authors.initials: MN
authors.lastname: Hall
authors.forename: E
authors.initials: E
authors.lastname: Gottlieb
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000596:Amino Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D046912:Multiprotein Complexes; D011393:Procollagen-Proline Dioxygenase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases