Influence of the Heme Nitric Oxide/Oxygen Binding Protein (H-NOX) on Cell Cycle Regulation in Caulobacter crescentus.

The ability of an organism to respond to environmental changes is paramount to survival across a range of conditions. The bacterial heme nitric oxide/oxygen binding proteins (H-NOX) are a family of biofilm-regulating gas sensors that enable bacteria to respond accordingly to the cytotoxic molecule nitric oxide. By interacting with downstream signaling partners, H-NOX regulates the production of the bacterial secondary messenger cyclic diguanylate monophosphate (c-di-GMP) to influence biofilm formation. The aquatic organism Caulobacter crescentus has the propensity to attach to surfaces as part of its transition into the stalked S-phase of its life cycle. This behavior is heavily influenced by intracellular c-di-GMP and thus poses H-NOX as a potential influencer of C. crescentus surface attachment and cell cycle. By generating a strain of C. crescentus lacking hnox, our laboratory has demonstrated that this strain exhibits a considerable growth deficit, an increase in biofilm formation, and an elevation in c-di-GMP. Furthermore, in our comprehensive proteome study of 2779 proteins, 236 proteins were identified that exhibited differential expression in Δhnox C. crescentus, with 132 being downregulated and 104 being upregulated, as determined by a fold change of ≥1.5 or ≤0.66 and a p value ≤0.05. Our systematic analysis unveiled several regulated candidates including GcrA, PopA, RsaA, FtsL, DipM, FlgC, and CpaE that are associated with the regulation of the cellular division process, surface proteins, flagellum, and pili assembly. Further examination of Gene Ontology and pathways indicated that the key differences could be attributed to several metabolic processes. Taken together, our data indicate a role for the HNOX protein in C. crescentus cell cycle progression.

H-NOX proteins in the virulence of pathogenic bacteria.

Nitric oxide (NO) is a toxic gas encountered by bacteria as a product of their own metabolism or as a result of a host immune response. Non-toxic concentrations of NO have been shown to initiate changes in bacterial behaviors such as the transition between planktonic and biofilm-associated lifestyles. The heme nitric oxide/oxygen binding proteins (H-NOX) are a widespread family of bacterial heme-based NO sensors that regulate biofilm formation in response to NO. The presence of H-NOX in several human pathogens combined with the importance of planktonic-biofilm transitions to virulence suggests that H-NOX sensing may be an important virulence factor in these organisms. Here we review the recent data on H-NOX NO signaling pathways with an emphasis on H-NOX homologs from pathogens and commensal organisms. The current state of the field is somewhat ambiguous regarding the role of H-NOX in pathogenesis. However, it is clear that H-NOX regulates biofilm in response to environmental factors and may promote persistence in the environments that serve as reservoirs for these pathogens. Finally, the evidence that large subgroups of H-NOX proteins may sense environmental signals besides NO is discussed within the context of a phylogenetic analysis of this large and diverse family.