C-elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation

HIF is a transcriptional complex that plays a central role in mammalian oxy gen homeostasis. Recent studies have defined posttranslational modification by prolyl hydroxylation as a key regulatory event that targets HIF-alpha. subunits for proteasomal destruction via the von Hippel-Lindau ubiquitylati on complex. Here, we define a conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans, and use a genetic approach to identify EGL-9 as a dioxygenas e that regulates HIF by prolyl hydroxylation. In mammalian cells, we show t hat the HIF-prolyl hydroxylases are represented by a series of isoforms bea ring a conserved 2-histidine-1-carboxylate iron coordination motif at the c atalytic site. Direct modulation of recombinant enzyme activity by graded h ypoxia, iron chelation, and cobaltous ions mirrors the characteristics of H IF induction in vivo, fulfilling requirements for these enzymes being oxyge n sensors that regulate HIF.