CYSL-1 Interacts with the O2-Sensing Hydroxylase EGL-9 to Promote H2S-Modulated Hypoxia-Induced Behavioral Plasticity in C. elegans

SummaryThe C. elegans HIF-1 proline hydroxylase EGL-9 functions as an O2 sensor in an evolutionarily conserved pathway for adaptation to hypoxia. H2S accumulates during hypoxia and promotes HIF-1 activity, but how H2S signals are perceived and transmitted to modulate HIF-1 and animal behavior is unknown. We report that the experience of hypoxia modifies a C. elegans locomotive behavioral response to O2 through the EGL-9 pathway. From genetic screens to identify novel regulators of EGL-9-mediated behavioral plasticity, we isolated mutations of the gene cysl-1, which encodes a C. elegans homolog of sulfhydrylases/cysteine synthases. Hypoxia-dependent behavioral modulation and H2S-induced HIF-1 activation require the direct physical interaction of CYSL-1 with the EGL-9 C terminus. Sequestration of EGL-9 by CYSL-1 and inhibition of EGL-9-mediated hydroxylation by hypoxia together promote neuronal HIF-1 activation to modulate behavior. These findings demonstrate that CYSL-1 acts to transduce signals from H2S to EGL-9 to regulate O2-dependent behavioral plasticity in C. elegans.

► Experience of hypoxia induces an EGL-9-mediated behavioral plasticity in C. elegans ► CYSL-1 is a regulator of the O2-sensing hydroxylase EGL-9 ► H2S-modulated interaction between CYSL-1 and EGL-9 mediates behavioral plasticity ► A conserved genetic pathway from CYSL-1 to EGL-9 mediates H2S signaling to HIF-1