The study was funded by Canadian Institutes of Health Research (grant MOP 106467) and Michael Smith Foundation of Health Research Career Scholar salary award to ERS.
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.
26Zinc is essential for cellular functions as it is a catalytic and structural component of many 27 proteins. In contrast, cadmium is not required in biological systems and is toxic. Zinc and cadmium 28 levels are closely monitored and regulated as their excess causes cell stress. To maintain homeostasis, 29 organisms induce metal detoxification gene programs through stress responsive transcriptional 30 regulatory complexes. In Caenorhabditis elegans, the MDT-15 subunit of the evolutionarily conserved 31Mediator transcriptional coregulator is required to induce genes upon exposure to excess zinc and 32 cadmium. However, the regulatory partners of MDT-15 in this response, its role in cellular and 33 physiological stress adaptation, and the putative role mammalian for MED15 in the metal stress 34 responses remain unknown. Here, we show that MDT-15 interacts physically and functionally with the 35Nuclear Hormone Receptor HIZR-1 to promote molecular, cellular, and organismal adaptation to 36 excess metals. Using gain-and loss-of-function mutants and qPCR and reporter analysis, we find that 37 mdt-15 and hizr-1 cooperate to induce zinc and cadmium responsive genes. Moreover, the two proteins 38 interact physically in yeast-two-hybrid assays and this interaction is enhanced by the addition of zinc or 39 cadmium, the former a known ligand of HIZR-1. Functionally, mdt-15 and hizr-1 mutants show 40 defective storage of excess zinc in the gut, and at the organismal level, mdt-15 mutants are 41 hypersensitive to zinc-and cadmium-induced reductions in egg-laying. Lastly, mammalian MDT-15 42 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a metal-43 stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung 44 adenocarcinoma cells exposed to cadmium. Collectively, our data show that mdt-15 and hizr-1 45 cooperate to regulate metal detoxification and zinc storage and that this mechanism appears to be at 46 least partially conserved in mammals. 48In their habitats, biological organisms encounter many metals, including essential 49 micronutrients such as iron, zinc, copper, and manganese, and toxic metals such as cadmium, mercury, 50 lead, and arsenic. Zinc is an essential trace element that plays a crucial role in numerous cellular and 51 physiological processes (1). It has a structural role in metabolic enzymes, growth factors, and 52 transcriptional regulators such as zinc finger proteins, and is also an enzymatic cofactor and a signaling 53 molecule (2,3). Accordingly, zinc is necessary for the function of approximately 10% of proteins in the 54 human proteome and approximately 8% of proteins in the nematode worm Caenorhabditis elegans (4). 55
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