Cadmium hijacks the high zinc response by binding and activating the HIZR-1 nuclear receptor.

Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In Caenorhabditis elegans, high zinc homeostasis is regulated by the high zinc activated nuclear receptor (HIZR-1) transcription factor. To define relationships between the responses to high zinc and cadmium, we analyzed transcription. Many genes were activated by both high zinc and cadmium, and hizr-1 was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require hizr-1, indicating there are at least two mechanisms of cadmium-regulated transcription. Cadmium directly bound HIZR-1, promoted nuclear accumulation of HIZR-1 in intestinal cells, and activated HIZR-1-mediated transcription via the high zinc activation (HZA) enhancer. Thus, cadmium binding promotes HIZR-1 activity, indicating that cadmium acts as a zinc mimetic to hijack the high zinc response. To elucidate the relationships between high zinc and cadmium detoxification, we analyzed genes that function in three pathways: the pcs-1/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the hizr-1/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the mek-1/sek-1/kinase signaling pathway promoted resistance to high zinc and cadmium. These studies identify resistance pathways that are specific for high zinc and cadmium, as well as a shared pathway.

Histidine protects against zinc and nickel toxicity in Caenorhabditis elegans.

Zinc is an essential trace element involved in a wide range of biological processes and human diseases. Zinc excess is deleterious, and animals require mechanisms to protect against zinc toxicity. To identify genes that modulate zinc tolerance, we performed a forward genetic screen for Caenorhabditis elegans mutants that were resistant to zinc toxicity. Here we demonstrate that mutations of the C. elegans histidine ammonia lyase (haly-1) gene promote zinc tolerance. C. elegans haly-1 encodes a protein that is homologous to vertebrate HAL, an enzyme that converts histidine to urocanic acid. haly-1 mutant animals displayed elevated levels of histidine, indicating that C. elegans HALY-1 protein is an enzyme involved in histidine catabolism. These results suggest the model that elevated histidine chelates zinc and thereby reduces zinc toxicity. Supporting this hypothesis, we demonstrated that dietary histidine promotes zinc tolerance. Nickel is another metal that binds histidine with high affinity. We demonstrated that haly-1 mutant animals are resistant to nickel toxicity and dietary histidine promotes nickel tolerance in wild-type animals. These studies identify a novel role for haly-1 and histidine in zinc metabolism and may be relevant for other animals.

The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan.

Ethosuximide is a medication used to treat seizure disorders in humans, and we previously demonstrated that ethosuximide can delay age-related changes and extend the lifespan of the nematode Caenorhabditis elegans. The mechanism of action of ethosuximide in lifespan extension is unknown, and elucidating how ethosuximide functions is important for defining endogenous processes that influence lifespan and for exploring the potential of ethosuximide as a therapeutic for age-related diseases. To identify genes that mediate the activity of ethosuximide, we conducted a genetic screen and identified mutations in two genes, che-3 and osm-3, that cause resistance to ethosuximide-mediated toxicity. Mutations in che-3 and osm-3 cause defects in overlapping sets of chemosensory neurons, resulting in defective chemosensation and an extended lifespan. These findings suggest that ethosuximide extends lifespan by inhibiting the function of specific chemosensory neurons. This model is supported by the observation that ethosuximide-treated animals displayed numerous phenotypic similarities with mutants that have chemosensory defects, indicating that ethosuximide inhibits chemosensory function. Furthermore, ethosuximide extends lifespan by inhibiting chemosensation, since the long-lived osm-3 mutants were resistant to the lifespan extension caused by ethosuximide. These studies demonstrate a novel mechanism of action for a lifespan-extending drug and indicate that sensory perception has a critical role in controlling lifespan. Sensory perception also influences the lifespan of Drosophila, suggesting that sensory perception has an evolutionarily conserved role in lifespan control. These studies highlight the potential of ethosuximide and related drugs that modulate sensory perception to extend lifespan in diverse animals.