CHAPTER 6: The Role of 2-Oxoglutarate-Dependent Oxygenases in Hypoxia Sensing
Published:23 Apr 2015
S. E. Wilkins, E. Flashman, J. S. Scotti, R. J. Hopkinson, R. Chowdhury, and C. J. Schofield, in 2-Oxoglutarate-Dependent Oxygenases, ed. C. Schofield and R. Hausinger, The Royal Society of Chemistry, 2015, pp. 169-209.
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Animals respond to chronic limiting oxygen availability by activation of the hypoxia inducible factor (HIF) system. As shown by pioneering work on erythropoietin regulation, HIF is an α,β-heterodimeric transcription factor which contains basic-helix-loop-helix PAS domains that bind to hypoxia response elements associated with hundreds of human genes. Both the levels and activity of HIF isoforms are affected by their post-translational hydroxylation that is catalysed by the HIF-α hydroxylases, which are Fe(ii)- and 2-oxoglutarate (2OG)-dependent oxygenases. The HIF prolyl hydroxylases (PHDs or EGLN enzymes) catalyse C-4 trans-hydroxylation of prolyl residues in the C- and N-terminal oxygen-dependent degradation domains in HIF-α. These modifications signal for substantially increased HIF-α degradation via the proteasome system by promoting the binding of HIF-α to the von Hippel Lindau protein, which is a targeting component for a ubiquitin E3 ligase. There is accumulating evidence that the activity of the PHDs is limited by oxygen availability. Thus, it is proposed that degradation of HIF-α is limited by oxygen availability, at least in many normal circumstances, and the PHDs act as hypoxia sensors. In a second mechanism of 2OG-dependent oxygenase mediated control of HIF, factor inhibiting HIF (FIH) catalyses asparaginyl hydroxylation in the C-terminal transcriptional activation domain of HIF-α, a modification that reduces the interaction of HIF with transcriptional co-activator proteins, and so reduces the transcription of HIF target genes. Inhibition of the HIF hydroxylases leads to upregulation of HIF target gene expression. PHD inhibitors are presently in trials for the treatment of anaemia via upregulation of erythropoietin. This chapter focuses on the biochemical roles of the HIF hydroxylases in the hypoxic response in animals and it describes how the discovery of the roles of the 2OG-dependent oxygenases in signalling hypoxia has promoted work on their roles in other aspects of the regulation of protein biosynthesis, at both transcriptional and translational levels.