QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 20, Issue 12, 2810-2819, June 15, 2009

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-10-1084v1 20/12/2810    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jensen, L. T. Articles by Culotta, V. C. Search for Related Content PubMed PubMed Citation Articles by Jensen, L. T. Articles by Culotta, V. C.

Down-Regulation of a Manganese Transporter in the Face of Metal Toxicity

Laran T. Jensen^*, Mark C. Carroll^*, Matthew D. Hall^*,, Christopher J. Harvey^*, Sara E. Beese, and Valeria C. Culotta^*

*Department of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205

Submitted October 30, 2008; Revised March 24, 2009; Accepted April 8, 2009
Monitoring Editor: Patrick J. Brennwald

The yeast Smf1p Nramp manganese transporter is posttranslationally regulated by environmental manganese. Smf1p is stabilized at the cell surface with manganese starvation, but is largely degraded in the vacuole with physiological manganese through a mechanism involving the Rsp5p adaptor complex Bsd2p/Tre1p/Tre2p. We now describe an additional level of Smf1p regulation that occurs with toxicity from manganese, but not other essential metals. This regulation is largely Smf1p-specific. As with physiological manganese, toxic manganese triggers vacuolar degradation of Smf1p by trafficking through the multivesicular body. However, regulation by toxic manganese does not involve Bsd2p/Tre1p/Tre2p. Toxic manganese triggers both endocytosis of cell surface Smf1p and vacuolar targeting of intracellular Smf1p through the exocytic pathway. Notably, the kinetics of vacuolar targeting for Smf1p are relatively slow with toxic manganese and require prolonged exposures to the metal. Down-regulation of Smf1p by toxic manganese does not require transport activity of Smf1p, whereas such transport activity is needed for Smf1p regulation by manganese starvation. Furthermore, the responses to manganese starvation and manganese toxicity involve separate cellular compartments. We provide evidence that manganese starvation is sensed within the lumen of the secretory pathway, whereas manganese toxicity is sensed within an extra-Golgi/cytosolic compartment of the cell.

Present address: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Address correspondence to: Laran T. Jensen (ljensen{at}jhsph.edu)

Abbreviations used: MVB, multivesicular body.