Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada;
Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):8966-8971. doi: 10.1073/pnas.1808393115. Epub 2018 Aug 20.
is a human pathogen that infects the stomach, where it experiences variable pH. To survive the acidic gastric conditions, produces large quantities of urease, a nickel enzyme that hydrolyzes urea to ammonia, which neutralizes the local environment. One of the regulators of urease expression in is HpNikR, a nickel-responsive transcription factor. Here we show that HpNikR also regulates urease expression in response to changes in pH, linking acid adaptation and nickel homeostasis. Upon measuring the cytosolic pH of exposed to an external pH of 2, similar to the acidic shock conditions that occur in the human stomach, a significant drop in internal pH was observed. This decrease in internal pH resulted in HpNikR-dependent activation of transcription. Furthermore, analysis of a slate of genes encoding other acid adaptation or nickel homeostasis components revealed HpNikR-dependent regulation in response to acid shock. This regulation was consistent with pH-dependent DNA binding to the corresponding promoter sequences observed in vitro with purified HpNikR. These results demonstrate that HpNikR can directly respond to changes in cytosolic pH during acid acclimation and illustrate the exquisitely coordinated regulatory networks that support infections in the harsh environment of the human stomach.
是一种感染胃部的人类病原体，胃部的 pH 值变化不定。为了在酸性胃液环境中存活，产生大量的脲酶，一种将尿素水解为氨的镍酶，从而中和局部环境。 中脲酶表达的一个调节因子是 HpNikR，一种镍反应转录因子。在这里，我们表明 HpNikR 还可以响应 pH 值的变化来调节脲酶的表达，从而将酸适应和镍稳态联系起来。在测量暴露于外部 pH 值为 2 的条件下的胞质 pH 值时，类似于在人类胃中发生的酸性冲击条件，观察到内部 pH 值的显著下降。这种内部 pH 值的降低导致 HpNikR 依赖性的 转录激活。此外，对一系列编码其他酸适应或镍稳态成分的 基因进行分析，发现酸冲击时存在 HpNikR 依赖性调节。这种调节与体外用纯化的 HpNikR 观察到的对应启动子序列的 pH 值依赖性 DNA 结合一致。这些结果表明，HpNikR 可以在酸适应过程中直接响应胞质 pH 值的变化，并说明了支持 在人类胃恶劣环境中感染的高度协调的调控网络。
