Acid-responsive activity of the metalloregulator NikR.

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.