From a genome-scale genetic screen, we have identified 114 lithium-sensitive and 6 lithium-tolerant gene mutations in Saccharomyces cerevisiae. Twenty-five of these identified lithium-sensitive mutations are of genes previously reported to be involved in sporulation and meiosis, whereas thirty-six of them are of genes involved in the vacuolar protein sorting (VPS) pathway, mainly functioning in the membrane docking and fusion. Accordingly, the lithium-sensitive phenotypes for one third of identified VPS mutants well correlate to their intracellular lithium contents in response to lithium stress. This indicates the integrity of the VPS pathway is critic for the ion homeostasis in yeast cells. The halotolerant protein kinase Hal5p, a regulator of the potassium transporter Trk1p, is shown to be the high-copy suppressor of nearly one third of identified lithium-sensitive mutations of genes involved in the sporulation and meiosis as well as in the biosynthesis of ergosterol. These results suggest that Hal5p-mediated ion homeostasis is important for these two biological processes.
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