Hypoxia-inducible factor induces cysteine dioxygenase and promotes cysteine homeostasis in Caenorhabditis elegans

<p>Dedicated genetic pathways regulate cysteine homeostasis. For example, high levels of cysteine activate cysteine dioxygenase, a key enzyme in cysteine catabolism in most animal and many fungal species. The mechanism by which cysteine dioxygenase is regulated is largely unknown. In an unbiased genetic screen for mutations that activate cysteine dioxygenase (<em>cdo-1</em>) in the nematode <em>C. elegans, </em>we isolated loss-of-function mutations in <em>rhy-1 </em>and <em>egl-9, </em>which encode proteins that negatively regulate the stability or activity of the oxygen-sensing hypoxia-inducible transcription factor (<em>hif-1</em>). EGL-9 and HIF-1 are core members of the conserved eukaryotic hypoxia response. However, we demonstrate that the mechanism of HIF-1-mediated induction of <em>cdo-1 </em>is largely independent of EGL-9 prolyl hydroxylase activity and the von Hippel-Lindau E3 ubiquitin ligase, the classical hypoxia signaling pathway components. We demonstrate that <em>C. elegans cdo-1 </em>is transcriptionally activated by high levels of cysteine and <em>hif-1</em>. <em>hif-1-</em>dependent activation of <em>cdo-1</em> occurs downstream of an H₂S-sensing pathway that includes <em>rhy-1, cysl-1, </em>and <em>egl-9.</em> <em>cdo-1 </em>transcription is primarily activated in the hypodermis where it is also sufficient to drive sulfur amino acid metabolism. Thus, the regulation of <em>cdo-1 </em>by <em>hif-1 </em>reveals a negative feedback loop that maintains cysteine homeostasis. High levels of cysteine stimulate the production of an H₂S signal. H₂S then acts through the <em>rhy-1/cysl-1/egl-9 </em>signaling pathway to increase HIF-1-mediated transcription of <em>cdo-1, </em>promoting the degradation of cysteine via CDO-1.</p>