|Thannhauser, Theodore - Ted|
Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/20/2008
Publication Date: 1/2/2009
Citation: Sooksa-Nguan, T., Yakubov, B., Kozlovskyy, V.I., Barcume, C.M., Thannhauser, T.W., Rutzke, M.A., Hart, J.J., Kochian, L.V., Vatamaniuk, O.K. 2009. Drosophila ABC Transporter DmHMT-1 Confers Tolerance to Cadmium. Journal of Biological Chemistry. 284:354-362. Interpretive Summary: Although the adverse health effects of heavy metals have been known for a long time, exposure to heavy metals continues and even is increasing in some areas, due to their continued production and emission into the environment from mining, smelting, electroplating, and the use of products such as fertilizers, nickel/cadmium batteries, pigments, and plastics. Since heavy metals are not biodegradable and have a low excretion rate (e.g. cadmium has a biological half-life of 15-30 years), exposure to heavy metals leads to their accumulation in vital organs, causing various disease states, including neurodegenerative conditions and cancer. At the cellular level, the toxicity of heavy metals results from the displacement of naturally occurring co-factors from their cellular binding sites, resulting in damaged proteins and enzymes, and promotion of the formation of toxic reactive oxygen species. Understanding the cellular mechanisms of metal detoxification is critical for the cure and prevention of heavy metal-caused diseases and for developing effective strategies for remediation of contaminated environments using plants. In this study, a number of model systems for human and plant heavy metal uptake and detoxification were used, including yeast the fruit fly, and worms. Clear data was presented that the transporter HMT1 (heavy metal tolerance factor 1) is a heavy metal transporter and is specifically involved in detoxification of cadmium. These new findings suggest that this transporter may play a key role in diverse aspects of heavy metal biology, including heavy metal accumulation in plants, and heavy metal-related diseases in humans.
Technical Abstract: Half molecule ATP-binding cassette transporters of the HMT1(heavy metal tolerance factor 1)subfamily are required for Cd2+ tolerance in Schizosaccharomyces pombe, Caenorhabditis elegans and Chlamydomonas reinhardtii, and have homologs in other species, including plants and humans. Based on studies in S. pombe, it has been proposed that HMT1 transports heavy meta-phytochelatin (PC) conjugates into vacuoles. PCs are glutathione derivatives that are synthesized by PC synthases (PCS) in plants, fungi and C. elegans in the presence of heavy metals. Our studies in C. elegans, however, suggested that HMT1 and PCS do not act together in metal detoxification. To resolve this discrepancy, we tested whether DrHMT1, an HMT1 from Drosophila whose genome lacks PCS homologs, functions in heavy metal detoxification. In so doing, we demonstrated for the first time that HMT1 from a higher animal functions in detoxification of Cd2+: heterologously-expressed DrHMT1 rescues Cd2+ hypersensitivity of S.pombe hmt-1 mutants and resides on the vacuolar membrane, but does not transport Cd-PC complexes. Parallel studies of hmt-1 S. pombe mutants led to unexpected findings: SpHMT1 either does not transport Cd-PC complexes or is not the sole Cd-PC transporter. Consistent with this discovery and with our suggestion that HMT1 and PCS operate in different detoxification pathways, we demonstrated that unlike PCS-deficient cells, SpHMT1 deficiency results in hypersensitivity only to Cd2+, but not to Hg2+ or As3+. Our findings significantly change the current understanding of HMT1 protein function and suggest a unique and conserved role for HMT1 in detoxification of Cd2+ in different species, including plants and humans.