Johnston Nichole R, Nallur Sunitha, Gordon Patricia B, Smith Kathryn D, Strobel Scott A
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, United States.
Department of Chemistry, Yale University, New Haven, CT, United States.
Front Microbiol. 2020 Jun 25;11:1410. doi: 10.3389/fmicb.2020.01410. eCollection 2020.
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 . 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.
氢氟酸通过一种长期以来被认为与氟化物对金属的高亲和力相关的机制引发细胞周期停滞。然而，我们最近发现，氟化物暴露引起的酸胁迫足以引发许多氟化物毒性的标志性表型。在这里，我们报告了使用基因组缺失文库对参与氟化物抗性和一般酸抗性的基因进行的系统筛选。我们将这些与多种酸——2,4-二硝基苯酚、羰基氰化物间氯苯腙（FCCP）、盐酸和硫酸——进行比较，这些酸都没有高金属亲和力。参与内吞作用、囊泡运输、pH维持和液泡功能的途径对氟化物耐受性尤为重要。大多数赋予氟化物胁迫抗性的基因也增强了对一般酸毒性的抗性。其表达调节高尔基体介导的囊泡运输的基因对氟化物抗性具有特异性，并且可能与氟化物-金属相互作用有关。这些结果支持了酸度是氟化物毒性机制中一个重要但未被充分认识的原理这一观点。
