title: HIF-1 is required for heat acclimation in the nematode Caenorhabditis elegans.
abstract: Chronic exposure to environmental heat improves tolerance via heat acclimation (AC). Our previous data on mammals indicate that reprogramming the expression of genes coding for stress proteins and energy-metabolism enzymes plays a major role. Knowledge of pathways leading to AC is limited. For their identification, we established a Caenorhabditis elegans AC model and tested mutants in which signaling pathways pertinent to acclimatory responses are mutated. AC attained by maintaining adult C. elegans at 25 degrees C for 18 h enhanced heat endurance of wild-type worms subjected to heat stress (35 degrees C) and conferred protection against hypoxia and cadmium. Survival curves demonstrated that both daf-2 (insulin receptor pathway) showing enhanced heat tolerance and daf-16 loss-of-function (a transcription factor mediating DAF-2 signaling) mutants benefit from AC, suggesting that the insulin receptor pathway does not mediate AC. In contrast, the hif-1 (hypoxia inducible factor) loss-of-function strain did not show acclimation, and non-acclimated vhl-1 and egl-9 mutants (overexpressing HIF-1) had greater heat endurance than the wild type. Like mammals, HIF-1 and HSP72 levels increased in the wild-type AC nematodes. HSP72 upregulation in AC hif-1 mutants was also observed; however, it was insufficient to improve heat/stress tolerance, suggesting that HIF-1 upregulation is essential for acclimation, whereas HSP72 upregulation in the absence of HIF-1 is inadequate. We conclude that HIF-1 upregulation is both an evolutionarily conserved and a necessary component of heat acclimation. The known targets of HIF-1 imply that metabolic adaptations are essential for AC-dependent tolerance to heat and heavy metals, in addition to their known role in hypoxic adaptation.
authors.affiliation: Department of Physiology, Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Millet
authors.initials: M
authors.lastname: Treinin
authors.forename: Judith
authors.initials: J
authors.lastname: Shliar
authors.forename: Huaqi
authors.initials: H
authors.lastname: Jiang
authors.forename: Jo Anne
authors.initials: JA
authors.lastname: Powell-Coffman
authors.forename: Zohar
authors.initials: Z
authors.lastname: Bromberg
authors.forename: Michal
authors.initials: M
authors.lastname: Horowitz
mesh_terms: D000064:Acclimatization / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002104:Cadmium / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D017238:Genes, Helminth / Q000235:genetics / Q000502:physiology; D006358:Hot Temperature; D051793:Hypoxia-Inducible Factor 1; D019216:Metals, Heavy / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016019:Survival Analysis; D014157:Transcription Factors
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D019216:Metals, Heavy; D009687:Nuclear Proteins; D014157:Transcription Factors; D002104:Cadmium; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin