title: CYSL-1 interacts with the O2-sensing hydroxylase EGL-9 to promote H2S-modulated hypoxia-induced behavioral plasticity in C. elegans.
abstract: The C. elegans HIF-1 proline hydroxylase EGL-9 functions as an O(2) sensor in an evolutionarily conserved pathway for adaptation to hypoxia. H(2)S accumulates during hypoxia and promotes HIF-1 activity, but how H(2)S 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 O(2) 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 H(2)S-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 H(2)S to EGL-9 to regulate O(2)-dependent behavioral plasticity in C. elegans.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, and McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.
authors.forename: Dengke K
authors.initials: DK
authors.lastname: Ma
authors.forename: Roman
authors.initials: R
authors.lastname: Vozdek
authors.forename: Nikhil
authors.initials: N
authors.lastname: Bhatla
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D003547:Cysteine Synthase / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D000860:Hypoxia / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D008958:Models, Molecular; D008967:Molecular Biology; D016296:Mutagenesis / Q000235:genetics; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D020539:Sequence Analysis, Protein
chemical_list: D029742:Caenorhabditis elegans Proteins; C403074:Egl-9 protein, C elegans; D051793:Hypoxia-Inducible Factor 1; D010455:Peptides; D049452:Green Fluorescent Proteins; D003547:Cysteine Synthase; D010100:Oxygen; D006862:Hydrogen Sulfide