HIF-independent role of Prolyl Hydroxylases in the cellular response to amino acids

Duran, R.V., MacKenzie, E.D., Boulahbel, H., Frezza, C., Heiserich, L., Tardito, S. , Rocha, S., Hall, M.N. and Gottlieb, E. (2013) HIF-independent role of Prolyl Hydroxylases in the cellular response to amino acids. Oncogene, 32(38), pp. 4549-4556. (doi: 10.1038/onc.2012.465) (PMID:23085753) (PMCID:PMC3787797)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tardito, Dr Saverio and Boulahbel, Miss Houda and Heiserich, Ms Lisa and Frezza, Mr Christian and Duran, Dr Raul and Gottlieb, Professor Eyal and MacKenzie, Mrs Elaine
• Authors: Duran, R.V., MacKenzie, E.D., Boulahbel, H., Frezza, C., Heiserich, L., Tardito, S., Rocha, S., Hall, M.N., and Gottlieb, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogene
• Publisher: Nature Publishing Group
• ISSN: 0950-9232
• ISSN (Online): 1476-5594
• Published Online: 22 October 2012
• Copyright Holders: Copyright © 2013 Macmillan Publishers Limited
• First Published: First published in Oncogene 32(38): 4549-4556
• Publisher Policy: Reproduced under a Creative Commons License