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Vol. 17, Issue 10, 4400-4410, October 2006

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The MAPK Hog1p Modulates Fps1p-dependent Arsenite Uptake and Tolerance in Yeast

Michael Thorsen^*, Yujun Di^*, Carolina Tängemo^*,, Montserrat Morillas, Doryaneh Ahmadpour^*, Charlotte Van der Does^*,, Annemarie Wagner^||, Erik Johansson^*, Johan Boman^||, Francesc Posas, Robert Wysocki^¶, and Markus J. Tamás^*

*Department of Cell and Molecular Biology/Microbiology, Göteborg University, S-405 30 Göteborg, Sweden; Cell Signaling Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain; ^||Department of Chemistry, Atmospheric Science, Göteborg University, S-412 96, Göteborg, Sweden; and ^¶Institute of Genetics and Microbiology, Wroclaw University, 51-148 Wroclaw, Poland

Submitted April 17, 2006; Revised June 19, 2006; Accepted July 24, 2006
Monitoring Editor: Charles Boone

Arsenic is widely distributed in nature and all organisms possess regulatory mechanisms to evade toxicity and acquire tolerance. Yet, little is known about arsenic sensing and signaling mechanisms or about their impact on tolerance and detoxification systems. Here, we describe a novel role of the S. cerevisiae mitogen-activated protein kinase Hog1p in protecting cells during exposure to arsenite and the related metalloid antimonite. Cells impaired in Hog1p function are metalloid hypersensitive, whereas cells with elevated Hog1p activity display improved tolerance. Hog1p is phosphorylated in response to arsenite and this phosphorylation requires Ssk1p and Pbs2p. Arsenite-activated Hog1p remains primarily cytoplasmic and does not mediate a major transcriptional response. Instead, hog1 sensitivity is accompanied by elevated cellular arsenic levels and we demonstrate that increased arsenite influx is dependent on the aquaglyceroporin Fps1p. Fps1p is phosphorylated on threonine 231 in vivo and this phosphorylation critically affects Fps1p activity. Moreover, Hog1p is shown to affect Fps1p phosphorylation. Our data are the first to demonstrate Hog1p activation by metalloids and provides a mechanism by which this kinase contributes to tolerance acquisition. Understanding how arsenite/antimonite uptake and toxicity is modulated may prove of value for their use in medical therapy.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-04-0315) on August 2, 2006.

Present addresses: Cell Biology and Biophysics Unit, EMBL, D-69117 Heidelberg, Germany;

Plant Pathology, Swammerdam Institute for Life Sciences, University of Amsterdam, 1090 GB, Amsterdam, The Netherlands.

Address correspondence to: Markus J. Tamás (markus.tamas{at}gmm.gu.se)

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