Abstract
Hydrofluoric acid elicits cell cycle arrest through a mechanism that has long been presumed to be linked with the high affinity of fluoride to metals. However, we have recently found that the acid stress from fluoride exposure is sufficient to elicit many of the hallmark phenotypes of fluoride toxicity. Here we report the systematic screening of genes involved in fluoride resistance and general acid resistance using a genome deletion library in Saccharomyces cerevisiae. We compare these to a variety of acids – 2,4-dinitrophenol, FCCP, hydrochloric acid, and sulfuric acid – none of which has a high metal affinity. Pathways involved in endocytosis, vesicle trafficking, pH maintenance, and vacuolar function are of particular importance to fluoride tolerance. The majority of genes conferring resistance to fluoride stress also enhanced resistance to general acid toxicity. Genes whose expression regulate Golgi-mediated vesicle transport were specific to fluoride resistance, and may be linked with fluoride-metal interactions. These results support the notion that acidity is an important and underappreciated principle underlying the mechanisms of fluoride toxicity.
Highlights
Responsiveness to acid stress is an essential adaptation for microorganisms
We set out to distinguish which aspects of fluoride toxicity are most likely associated with acid stress rather than metalloprotein inhibition
In order to establish this distinction, we compared the results from fluoride exposure to those for exposure to HCl, H2SO4, FCCP, or 2,4-DNP; each of which elicit acid stress, but do not have a high affinity for metals
Summary
Responsiveness to acid stress is an essential adaptation for microorganisms. Unlike multicellular organisms in which internal, sensitive tissues are protected from toxicants, microbes are directly exposed to their environment. Fungi have proven quite successful in combating acid stress in particular; yeast grow optimally in pH 4.0–6.0 media, and have been reported to efficiently adapt to media with a pH as low as 2.5 (Narendranath and Power, 2005; Liu et al, 2015). Eukaryotic microbes, such as fungi, contain organelles for the compartmentalization and specialized functions in combating acid stress. The intracellular pH of the cytoplasm and organelles are tightly controlled by H+-ATPases, Pma1p, and V-ATPases (Kane, 2016) This regulation is critical for maintaining the function of intracellular proteins, many of which are sensitive to pH changes. Of particular sensitivity are transmembrane and metabolic enzymes, such as phosphate transporters, and phosphofructokinase (Hardewig et al, 1991; Ding et al, 2013)
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