PHDs overactivation during chronic hypoxia "desensitizes" HIFalpha and protects cells from necrosis.
Cell adaptation to changes in oxygen (O(2)) availability is controlled by two subfamilies of O(2)-dependent enzymes: the hypoxia inducible factor (HIF)-prolyl and asparaginyl hydroxylases [prolyl hydroxylases domain (PHDs) and factor inhibiting HIF (FIH)]. These oxygen sensors regulate the activity of the HIF, a transcriptional complex central in O(2) homeostasis. In well oxygenated cells, PHDs hydroxylate the HIFalpha subunits, thereby targeting them for proteasomal degradation. In contrast, acute hypoxia inhibits PHDs, leading to HIFalpha stabilisation. However, here we show that chronic hypoxia induces HIF1/2alpha"desensitization" in cellulo and in mice. At the basis of this general adaptative mechanism, we demonstrate that chronic hypoxia not only increases the pool of PHDs but also overactivates the three PHD isoforms. This overactivation appears to be mediated by an increase in intracellular O(2) availability consequent to the inhibition of mitochondrial respiration. By using in cellulo and in vivo siRNA, we found that the PHDs are the key enzymes triggering HIFalpha desensitization, a feedback mechanism required to protect cells against necrotic cell death and thus to adapt them across a chronic hypoxia. Hence, PHDs serve as dual enzymes, for which inactivation and later overactivation is necessary for cell survival in acute or chronic hypoxia, respectively.
Ginouvès
Amandine
A
Institute of Signaling, Developmental Biology, and Cancer Research, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6543, University of Nice, Centre Antoine Lacassagne, 06189 Nice, France.
Ilc
Karine
K
Macías
Nuria
N
Pouysségur
Jacques
J
Berra
Edurne
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010100:Oxygen / Q000494:pharmacology; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen