NikR-mediated regulation of Helicobacter pylori acid adaptation

Nickel is the cofactor of the Helicobacter pylori urease enzyme, a factor essential for the chronic colonization of the acidic hostile environment in the human stomach. The NikR regulatory protein directly controls urease expression and regulates the uptake of nickel, and is also able to regulate the expression of other regulatory proteins including the iron-responsive regulator Fur. Through regulatory crosstalk and overlapping regulons, the NikR protein controls the expression of many systems important for colonization and acid adaptation. Despite the paucity of regulatory proteins, this enables H. pylori to optimally adapt to conditions in the stomach, making it one of the most successful human pathogens.     

Nickel-binding and accessory proteins facilitating Ni-enzyme maturation in Helicobacter pylori

Helicobacter pylori colonizes the human gastric mucosa and this can lead to chronic gastritis, peptic and duodenal ulcers, and even gastric cancers. The bacterium colonizes over one-half of the worlds population. Nickel plays a major role in the bacteriums colonization and persistence attributes as two nickel enzyme sinks obligately contain the metal. Urease accounts for up to 10% of the total cellular protein made and is required for initial colonization processes, and the hydrogen oxidizing hydrogenase provides the bacterium a high-energy substrate yielding low potential electrons for energy generation. A battery of accessory proteins are needed for maturation or activation of each of the apoenzymes. These include Ni-chaperones and GTPases, some of which are unique to each Ni-enzyme and others that are individually required for maturation of both the Ni-enzymes. H. pylori’s need for some conventional hydrogenase maturation proteins playing roles in urease maturation may have to do with the poor nickel-sequestering ability of the UreE urease maturation protein compared to other systems. H. pylori also possesses a NixA nickel specific permease, a nickel dependent regulator (NikR), a recently identified nickel efflux system (CznABC), and a histidine-rich heat shock protein, HspA. Based on mutant analysis approaches all these proteins have roles in nickel homeostasis, in urease expression, and in host colonization. The His-rich putative nickel storage proteins Hpn and Hpn-like play roles in nickel detoxification and may influence the levels of Ni-activated urease that can be achieved.