TR_ACTIFS

Heavy metals such as cadmium stemming from human activities are major contaminants of our environment and are easily incorporated into trophic chains. In humans, where cadmium is known for its carcinogenic and teratogenic properties, its half-life is exceeding 20 years due to a very slow excretion rate. Surprisingly, membrane transporters responsible for the detoxification of heavy metals in kidney and liver are still unknown. In yeasts, ScYCF1 in Saccharomyces cerevisiae and SpHMT1 in Schyzosaccharomyces pombe are responsible for the cytosolic elimination of cadmium and its sequestration in the vacuole. Both transporters are functioning through different mechanisms but allow the cell to cope with the metal toxicity. The objectives of our project are 1) to identify the functional homologues of ScYCF1 and SpHMT1 in charge of cadmium elimination in the multicellular eukaryote zebra fish (Danio rerio); 2) to characterize these new transporters as well as their human counterparts after heterologous expression in the ycf1 S. cerevisiae strain or in the baculovirus Sf9/ insect cells systems; 3) to detail the role of human Tap1/Tap2 in immune disorders observed after cadmium exposition. The gathering of our 3 laboratories will combine environmental, cellular and molecular approaches in model organisms such as yeast or zebra fish, whose genomes are sequenced. Moreover, our consortium has already a good expertise in manipulating several heterologous expression systems, a necessary condition for the molecular description of these transporters. These competences will be complemented as an added value by the expertise of the third partner which is powerful in the structure-function analysis of membrane transporters. By the end, this project will allow the identification of active transporters involved in cadmium detoxification in vertebrates and a better characterization of transporters which function is only partially described (SpHMT1, HsTAP1/TAP2). The knowledge of the molecular mechanisms of metal transport in vertebrates will facilitate prevention and treatments of disorders due to metal assimilation but will also to help in the development of efficient methods for bioremediation of heavy metals in the environment.