Hypoxia-inducible factor promotes cysteine homeostasis in Caenorhabditis elegans .

The amino acid cysteine is critical for many aspects of life, yet excess cysteine is toxic. Therefore, animals require pathways to maintain cysteine homeostasis. In mammals, high cysteine activates cysteine dioxygenase, a key enzyme in cysteine catabolism. The mechanism by which cysteine dioxygenase is regulated remains largely unknown. We discovered that C. elegans cysteine dioxygenase ( cdo-1 ) is transcriptionally activated by high cysteine and the hypoxia inducible transcription factor ( hif-1 ). hif-1- dependent activation of cdo-1 occurs downstream of an H 2 S-sensing pathway that includes rhy-1, cysl-1 , and egl-9. cdo-1 transcription is primarily activated in the hypodermis where it is sufficient to drive sulfur amino acid metabolism. EGL-9 and HIF-1 are core members of the cellular hypoxia response. However, we demonstrate that the mechanism of HIF-1-mediated induction of cdo-1 functions largely independent of EGL-9 prolyl hydroxylation and the von Hippel-Lindau E3 ubiquitin ligase; classical hypoxia signaling pathway components. We propose that the intersection of hif-1 and cdo-1 reveals a negative feedback loop for maintaining cysteine homeostasis. High cysteine stimulates the production of an H 2 S signal. H 2 S then activates the rhy-1/cysl-1/egl-9 signaling pathway, increasing HIF-1-mediated transcription of cdo-1 , promoting degradation of cysteine via CDO-1.