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

Abstract

Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In <i>Caenorhabditis elegans</i>, 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 <i>hizr-1</i> was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require <i>hizr-1</i>, 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 <i>pcs-1</i>/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the <i>hizr-1</i>/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the <i>mek-1/sek-1/</i>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.