Zinc is an essential element involved in many biological processes and human disorders. Excess zinc is deleterious, and therefore animals have evolved sophisticated mechanisms to maintain zinc homeostasis in response to variable zinc availability. However, mechanisms of zinc sensing and detoxification are not well defined. Caenorhabditis elegans responds to excess dietary zinc by activating transcription of critical zinc-homeostasis genes, such as the zinc exporters cdf-2 and ttm-1b. We demonstrated that the transcriptional response to high dietary zinc is mediated by the high zinc activated (HZA) element, a 14 bp DNA enhancer that is present in multiple genes that are induced by high zinc (Roh et al., NAR, 2014). To identify genes that are necessary for the response to excess dietary zinc, we conducted a forward mutagenic screen for animals with defects in zinc-induced transcription. We identified five loss-of-function mutations and one gain-of-function mutation in nhr-33, which encodes an uncharacterized nuclear receptor. Nuclear receptors are transcription factors that have a DNA binding domain and a ligand binding domain. nhr-33(lf) mutations abrogate the induction of zinc-regulated genes and dramatically impair zinc homeostasis, as documented by reduced growth and development when mutant animals were cultured with excess dietary zinc. By contrast the nhr-33(gf) mutation caused constitutive induction of zinc-regulated genes. Thus, nhr-33 is necessary and sufficient for high zinc-activated transcription. To characterize the mechanism of action of nhr-33, we analyzed the expression pattern; NHR-33 is expressed in intestinal cells and accumulates in nuclei in response to high dietary zinc. Biochemical experiments demonstrated that NHR-33 binds the HZA element with high specificity. These results indicate that nhr-33 is the master regulator of high zinc homeostasis in C. elegans. High dietary zinc causes NHR-33 to accumulate in the nucleus where it binds the HZA element and activates transcription of genes that promote zinc homeostasis. These findings establish a new paradigm for environmental sensing by identifying a novel and unexpected role for a nuclear receptor in metal homeostasis.
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