Metal-responsive promoter DNA compaction by the ferric uptake regulator

Abstract

Short-range DNA looping has been proposed to affect promoter activity in many bacterial species and operator configurations, but only few examples have been experimentally investigated in molecular detail. Here we present evidence for a metal-responsive DNA condensation mechanism controlled by the Helicobacter pylori ferric uptake regulator (Fur), an orthologue of the widespread Fur family of prokaryotic metal-dependent regulators. H. pylori Fur represses the transcription of the essential arsRS acid acclimation operon through iron-responsive oligomerization and DNA compaction, encasing the arsR transcriptional start site in a repressive macromolecular complex. A second metal-dependent regulator NikR functions as nickel-dependent anti-repressor at this promoter, antagonizing the binding of Fur to the operator elements responsible for the DNA condensation. The results allow unifying H. pylori metal ion homeostasis and acid acclimation in a mechanistically coherent model, and demonstrate, for the first time, the existence of a selective metal-responsive DNA compaction mechanism controlling bacterial transcriptional regulation.

Acid-responsive activity of the Helicobacter pylori metalloregulator NikR

“…This lack of repression could be a consequence of the impact of nickel on the cytosolic pH ( Fig. 1, Right) or the influence of HpNikR on HpArsR activity, and highlights the integrated nature of the regulatory networks in this organism (13,42). Finally, transcription of the cahA gene and levels of the ComH protein have been reported to be acid-responsive (39,43), but under these conditions no impact of acid shock was detected in the wild-type cells and acid-dependent repression of cahA was observed in the ΔnikR knockout strain.…”

“…For instance, arsR and amiE are repressed by HpFur in an irondependent manner (42,54), and ureA, ureG, amiE, and amiF are coactivated by HpArsR (23,46). Furthermore, arsR is regulated through a complex mechanism involving HpNikR, HpFur, and HpArsR itself, suggesting that the expression of arsR is sensitive to the various stimuli that influence the activities of all three transcription factors (42). These overlapping regulons complicate the interpretation of the global expression data.…”

“…The milder impact on ceuE expression during acid shock without nickel supplementation, despite apo-HpNikR binding P ceuE under analogous conditions in vitro, implies that the degree of regulatory activity exerted by HpNikR during acid adaptation is also promoterspecific. Furthermore, there is no direct relationship between the location of HpNikR binding relative to the TSS and whether HpNikR activates or represses transcription, which in H. pylori is not a phenomenon unique to HpNikR (42,48,57).…”

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

“…While this may be true for complex promoters, e.g. the arsR promoter were the interaction of Fur and NikR governs a sofisticated signal integration logic52, this possibility does not explain the role of intracistronic binding sites. Tentatively, intragenically bound NikR could hint at nucleoid-associated functions important for chromosome organization53.…”

Pathogenesis of Helicobacter pylori infection

“…NikR is also a positive transcriptional regulator of ArsRS involved in acid adaptation. Roncarati et al 12 reported a metal-responsive promoter DNA compaction mechanism, which modulates the transcriptional regulation and coordinated response to environmental stimuli. In the presence of nickel, NikR antagonizes the Fur-mediated regulation and DNA compaction at the ArsRS promoter.…”