Abstract
Zinc is essential for cellular functions as it is a catalytic and structural component of many proteins. In contrast, cadmium is not required in biological systems and is toxic. Zinc and cadmium levels are closely monitored and regulated as their excess causes cell stress. To maintain homeostasis, organisms induce metal detoxification gene programs through stress responsive transcriptional regulatory complexes. In Caenorhabditis elegans, the MDT-15 subunit of the evolutionarily conserved Mediator transcriptional coregulator is required to induce genes upon exposure to excess zinc and cadmium. However, the regulatory partners of MDT-15 in this response, its role in cellular and physiological stress adaptation, and the putative role for mammalian MED15 in the metal stress responses remain unknown. Here, we show that MDT-15 interacts physically and functionally with the Nuclear Hormone Receptor HIZR-1 to promote molecular, cellular, and organismal adaptation to cadmium and excess zinc. Using gain- and loss-of-function mutants and qRT-PCR and reporter analysis, we find that mdt-15 and hizr-1 cooperate to induce zinc and cadmium responsive genes. Moreover, the two proteins interact physically in yeast-two-hybrid assays and this interaction is enhanced by the addition of zinc or cadmium, the former a known ligand of HIZR-1. Functionally, mdt-15 and hizr-1 mutants show defective storage of excess zinc in the gut and are hypersensitive to zinc-induced reductions in egg-laying. Furthermore, mdt-15 but not hizr-1 mutants are hypersensitive to cadmium-induced reductions in egg-laying, suggesting potential divergence of regulatory pathways. Lastly, mammalian MDT-15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a cadmium and zinc-stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung adenocarcinoma cells exposed to cadmium. Collectively, our data show that mdt-15 and hizr-1 cooperate to regulate cadmium detoxification and zinc storage and that this mechanism is at least partially conserved in mammals.
Highlights
In their habitats, biological organisms encounter many metals, including essential micronutrients such as zinc, iron, copper, and manganese, and toxic metals such as cadmium, mercury, lead, and arsenic
Using the roundworm Caenorhabditis elegans, we previously showed that the Mediator subunit MDT-15 is essential in many cytoprotective responses including that against excess zinc or cadmium
We find that the nuclear receptor high-zinc– activated nuclear receptor 1 (HIZR-1), shown previously to convey high zinc detoxification, works together with MDT-15 to protect worms against high zinc as well as cadmium by cooperatively activating a cytoprotective gene expression program
Summary
Biological organisms encounter many metals, including essential micronutrients such as zinc, iron, copper, and manganese, and toxic metals such as cadmium, mercury, lead, and arsenic. Zinc is an essential trace element that plays a crucial role in numerous cellular and physiological processes [1]. It has a structural role in metabolic enzymes, growth factors, and zinc finger proteins, and is an enzymatic cofactor and a signaling molecule [2,3]. Rare and generally associated with decreased copper uptake and associated deficiency, exposure to high doses of zinc is detrimental, as it has toxic effects, causes cell stress, and alters physiological programs such as systemic growth, immune responses, and neuro-sensory and endocrine functions [5]
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