Department of Cell and Molecular Biology-Microbiology, Goteborg University, S-405 30 Goteborg, Sweden-
Abstract: 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, hog1delta 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-