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Acid-responsive activity of the Helicobacter pylori metalloregulator NikR

Michael D. Jones,Yanjie Li,D. Zamble

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance The acid adaptation systems of the pathogen Helicobacter pylori are complex and critical to the survival of this bacterium in the harsh environment of the human stomach. One of the relatively few transcription factors in H. pylori is HpNikR, a metal-responsive protein that controls homeostasis of nickel, an essential nutrient for this organism. In this study, we show that HpNikR also regulates gene expression in direct response to acidic pH. Exposure of H. pylori to acid shock conditions depresses its cytosolic pH, which activates the regulation of multiple promoters by HpNikR. These results demonstrate that HpNikR has a multifaceted response that links nickel homeostasis and acid acclimation, two critical functions in this infectious organism. Helicobacter pylori is a human pathogen that infects the stomach, where it experiences variable pH. To survive the acidic gastric conditions, H. pylori 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 H. pylori 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 H. pylori 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 ureA transcription. Furthermore, analysis of a slate of H. pylori 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 H. pylori infections in the harsh environment of the human stomach.

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