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J. Biol. Chem., Vol. 280, Issue 25, 23684-23690, June 24, 2005

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CeHMT-1, a Putative Phytochelatin Transporter, Is Required for Cadmium Tolerance in Caenorhabditis elegans^*

Olena K. Vatamaniuk, Elizabeth A. Bucher¶, Meera V. Sundaram, and Philip A. Rea||

From the Plant Science Institute, Department of Biology, University of Pennsylvania and the Departments of ^¶Cell and Developmental Biology and Genetics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Phytochelatins (PCs), (-Glu-Cys)_n Gly polymers that were formerly considered to be restricted to plants and some fungal systems, are now known to play a critical role in heavy metal (notably Cd²⁺) detoxification in Caenorhabditis elegans. In view of the functional equivalence of the gene encoding C. elegans PC synthase 1, ce-pcs-1, to its homologs from plant and fungal sources, we have gone on to explore processes downstream of PC fabrication in this organism. Here we describe the identification of a half-molecule ATP-binding cassette transporter, CeHMT-1, from C. elegans with an equivalent topology to that of the putative PC transporter SpHMT-1 from Schizosaccharomyces pombe. At one level, CeHMT-1 satisfies the requirements of a Cd²⁺ tolerance factor involved in the sequestration and/or elimination of Cd·PC complexes. Heterologous expression of cehmt-1 in S. pombe alleviates the Cd²⁺-hypersensitivity of hmt^– mutants concomitant with the localization of CeHMT-1 to the vacuolar membrane. Suppression of the expression of ce-hmt-1 in intact worms by RNA interference (RNAi) confers a Cd²⁺-hypersensitive phenotype similar to but more pronounced than that exhibited by ce-pcs-1 RNAi worms. At another level, it is evident from comparisons of the cell morphology of ce-hmt-1 and cepcs-1 single and double RNAi mutants that CeHMT-1 also contributes to Cd²⁺ tolerance in other ways. Whereas the intestinal epithelial cells of ce-pcs-1 RNAi worms undergo necrosis upon exposure to toxic levels of Cd²⁺, the corresponding cells of ce-hmt-1 RNAi worms instead elaborate punctate refractive inclusions within the vicinity of the nucleus. Moreover, a deficiency in CeHMT-1 does not interfere with the phenotype associated with CePCS-1 deficiency and vice versa. Double ce-hmt-1; ce-pcs-1 RNAi mutants exhibit both cell morphologies when exposed to Cd²⁺. These results and those from our previous investigations of the requirement for PC synthase for heavy metal tolerance in C. elegans demonstrate PC-dependent, HMT-1-mediated heavy metal detoxification not only in S. pombe but also in some invertebrates while at the same time indicating that the action of CeHMT-1 does not depend exclusively on PC synthesis.

Received for publication, March 28, 2005 , and in revised form, April 19, 2005.

^* This work was supported by National Science Foundation Grant MCB-0077838, United States Department of Energy Grant DE-FG02-91ER20055 (to P. A. R.), and National Institutes of Health Grant CA87512 (to M. V. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF497513, AF497514, and AAM33381

^|| To whom correspondence should be addressed: Plant Science Inst., Dept. of Biology, 3800 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104-6018. Tel.: 215-898-0807; Fax: 215-898-8780; E-mail: parea{at}sas.upenn.edu.

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