Hypoxia-inducible factor induces cysteine dioxygenase and promotes cysteine homeostasis inCaenorhabditis elegans

Abstract

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 thatC. eleganscysteine dioxygenase (cdo-1) is transcriptionally activated by high cysteine and the hypoxia inducible transcription factor (hif-1).hif-1-dependent activation ofcdo-1occurs downstream of an H2S-sensing pathway that includesrhy-1,cysl-1, andegl-9.cdo-1transcription 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 ofcdo-1functions 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 ofhif-1andcdo-1reveals a negative feedback loop for maintaining cysteine homeostasis. High cysteine stimulates the production of an H2S signal. H2S then activates therhy-1/cysl-1/egl-9signaling pathway, increasing HIF-1-mediated transcription ofcdo-1, promoting degradation of cysteine via CDO-1.