Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans

Autoři: Naomi Shomer aff001;  Alexandre Zacharie Kadhim aff001;  Jennifer Margaret Grants aff001;  Xuanjin Cheng aff002;  Deema Alhusari aff001;  Forum Bhanshali aff002;  Amy Fong-Yuk Poon aff002;  Michelle Ying Ya Lee aff002;  Anik Muhuri aff002;  Jung In Park aff002;  James Shih aff002;  Dongyeop Lee aff004;  Seung-Jae V. Lee aff005;  Francis Christopher Lynn aff003;  Stefan Taubert aff001
Působiště autorů: Graduate Program in Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada aff001;  Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada aff002;  British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada aff003;  Department of Life Sciences, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, South Korea aff004;  Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yuseong-Gu, Daejeon, South Korea aff005;  Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada aff006;  Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada aff007
Vyšlo v časopise: Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans. PLoS Genet 15(12): e1008508. doi:10.1371/journal.pgen.1008508
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008508


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.

Klíčová slova:

Cadmium – Caenorhabditis elegans – Gene expression – Gene regulation – RNA interference – Transcription factors – Transcriptional control – Zinc


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