CYSL-1 Interacts With the O2-sensing Hydroxylase EGL-9 to Promote H2S-modulated Hypoxia-Induced Behavioral Plasticity in C. Elegans

Neuron. 2012 Mar 8;73(5):925-40. doi: 10.1016/j.neuron.2011.12.037.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Computational Biology
  • Cysteine Synthase / genetics
  • Cysteine Synthase / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hydrogen Sulfide / pharmacology*
  • Hypoxia / drug therapy
  • Hypoxia / genetics
  • Hypoxia / physiopathology*
  • Hypoxia-Inducible Factor 1 / genetics
  • Hypoxia-Inducible Factor 1 / metabolism
  • Hypoxia-Inducible Factor 1 / pharmacology
  • Locomotion / drug effects*
  • Locomotion / genetics*
  • Locomotion / physiology
  • Models, Molecular
  • Molecular Biology
  • Mutagenesis / genetics
  • Oxygen / metabolism
  • Oxygen / pharmacology
  • Peptides / pharmacology
  • Sequence Analysis, Protein

Substances

  • Caenorhabditis elegans Proteins
  • Egl-9 protein, C elegans
  • Hypoxia-Inducible Factor 1
  • Peptides
  • Green Fluorescent Proteins
  • Cysteine Synthase
  • Oxygen
  • Hydrogen Sulfide