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

Significance Zinc is essential for animal life, and zinc levels are carefully regulated by homeostatic mechanisms. In the model organism Caenorhabditis elegans , the HIZR-1 nuclear receptor directly binds zinc and mediates high zinc homeostasis by regulating transcription. Cadmium is structurally similar to zinc but is a prevalent environmental toxin. Here, we explore how animals respond to these similar metals. The results suggest that cadmium hijacks the high zinc homeostasis response by directly binding and activating HIZR-1. This is an example of cadmium functioning as an activating ligand for a zinc-regulated protein in contrast to the prevailing model that cadmium binding causes protein dysfunction. These results elucidate the interplay between these two metals and reveal an unexpected mechanism of cadmium transcriptional control.