Comprehensive mapping of the Helicobacter pylori NikR regulon provides new insights in bacterial nickel responses

Abstract

Nickel homeostasis is important for pathogenic and ureolytic bacteria, which use this metal ion as enzymatic cofactor. For example, in the human pathogen Helicobacter pylori an optimal balance between nickel uptake and incorporation in metallo-enzymes is fundamental for colonization of the host. Nickel is also used as cofactor to modulate DNA binding of the NikR regulator, which controls transcription of genes involved in nickel trafficking or infection in many bacteria. Accordingly, there is much interest in a systematic characterization of NikR regulation. Herein we use H. pylori as a model to integrate RNA-seq and ChIP-seq data demonstrating that NikR not only regulates metal-ion transporters but also virulence factors, non-coding RNAs, as well as toxin-antitoxin systems in response to nickel stimulation. Altogether, results provide new insights into the pathobiology of H. pylori and contribute to understand the responses to nickel in other bacteria.

Genomics of Helicobacter pylori

“…32 Similar investigations using ChIP and RNA sequencing to systematically map the regulon of NikR revealed not only the known involvement of the Nickel regulator in metal homeostasis but also that NikR under nickel stimulation regulates virulence factors, toxin-antitoxin systems, and noncoding RNA. 33 Scavenging and controlling the homeostasis of nickel is of major importance for H. pylori, which both include the regulation of transporters and metal-binding proteins but also feedback loops regulating NikR itself. In contrast to HsrA, this study also revealed extensive intragenic binding by NikR.…”

Acid-responsive activity of the Helicobacter pylori metalloregulator NikR

“…To balance these opposing factors, H. pylori possesses a robust network of metalloregulation and nickel homeostasis systems, with the nickel-responsive transcription factor NikR playing a central role (11,12). H. pylori NikR (HpNikR) is an activator or repressor of a variety of genes encoding the urease precursor proteins as well as nickel transporters, nickel storage proteins, and others (13)(14)(15)(16)(17)(18). HpNikR enacts this activity via nickel-activated DNA binding to the corresponding promoters (18)(19)(20).…”

Pathogenesis of Helicobacter pylori infection

“…Another study attempted to uncouple direct versus indirect transcriptional effects of the nickel-responsive repressor NikR using a short, high pulse of nickel and a combination of RNA-seq and ChiP-seq. 37 This analysis suggested that some genes previously attributed to the NikR regulon are secondary targets through upregulation of Fur and noncoding RNAs. While the authors generally argued that NikR was not a global regulator, as only a subset of previous targets confirmed that they were able to identify two new OMPs in the NikR regulon.…”

“…As motility is downregulated during biofilm formation, the authors suggested that this points to the importance of FliM in regulating additional cellular processes. Another study attempted to uncouple direct versus indirect transcriptional effects of the nickel‐responsive repressor NikR using a short, high pulse of nickel and a combination of RNA‐seq and ChiP‐seq . This analysis suggested that some genes previously attributed to the NikR regulon are secondary targets through upregulation of Fur and noncoding RNAs.…”