Fur-mediated global regulatory circuits in pathogenic Neisseria species

Abstract

The ferric uptake regulator (Fur) protein has been shown to function as a repressor of transcription in a number of diverse microorganisms. However, recent studies have established that Fur can function at a global level as both an activator and a repressor of transcription through both direct and indirect mechanisms. Fur-mediated indirect activation occurs via the repression of additional repressor proteins, or small regulatory RNAs, thereby activating transcription of a previously silent gene. Fur mediates direct activation through binding of Fur to the promoter regions of genes. Whereas the repressive mechanism of Fur has been thoroughly investigated, emerging studies on direct and indirect Fur-mediated activation mechanisms have revealed novel global regulatory circuits.

Fig 1

Alignment of Fur orthologues from both Gram-negative and Gram-positive bacteria.

Fig 2

Mechanisms of Fur-mediated regulation. (A) Iron-bound Fur dimer binds to the −10 and −35 motifs in the promoter region, blocking binding of RNA polymerase and thus reducing transcription (left panel). Without iron, Fur does not bind to the promoter region, thereby allowing transcription via RNA polymerase (right panel). This mechanism has been well established by experimental evidence (32). (B) In the apo-Fur repression mechanism, when iron is present, Fur does not bind to the promoter region, resulting in transcription of the gene by RNA polymerase (left panel). Without iron, the apo-Fur dimer binds to the −10 and −35 motifs in the promoter region to inhibit binding of RNA polymerase and repress transcription (right panel). Apo-Fur repression was experimentally demonstrated in H. pylori (13, 72). (C) In the apo-Fur activation mechanism, Fur does not bind to the promoter region; thus, gene transcription is not active when iron is present (left panel). Without iron, the apo-Fur dimer binds to a site further upstream of the −10 and −35 motifs in the promoter region and upregulates transcription (right panel). This mechanism was first described in V. vulnificus (57). (D) Iron-bound Fur dimer binds to the promoter region and upregulates transcription (left panel). Without iron, Fur does not bind to the promoter region to initiate transcription (right panel). A few cases have been reported that indicate Fur-mediated direct activation through binding to defined promoter regions (50, 77, 105). (E) Iron-bound Fur dimer binds to −10 and −35 motifs in the promoter region and represses a negative regulator such as a protein repressor or a small RNA. Subsequently, genes that are repressed by the negative regulators are then transcribed and these genes show indirect Fur activation (left panel). Without iron and Fur repression, the negative regulators are transcribed and repress their target genes (right panel). Fur-repressed small RNAs have been reported in E. coli (–64), V. cholerae (21), P. aeruginosa (103), and B. subtilis (38) as well as in the two pathogenic Neisseria species (28, 65, 66). Known Fur-repressed protein regulators include H-NS in S. enterica serovar Typhimurium (95) and MpeR in N. gonorrhoeae (53).

Fig 3

Fur mediates direct activation via variable mechanisms. (A) An iron-bound Fur dimer binds to a site further upstream of −10 and −35 motifs in the promoter region and out-competes binding of a repressor protein, thus activating transcription (left panel). Without iron, Fur does not function and the repressor protein binds to the promoter region to repress gene transcription (right panel). Three examples have been reported in E. coli and N. gonorrhoeae (50, 77). (B) An iron-bound Fur dimer binds to a site overlapping the −10 and −35 motifs in the promoter region in order to recruit RNA polymerase to activate transcription (left panel). Without iron, Fur does not bind to the promoter region and RNA polymerase is not recruited to initiate transcription (right panel). This mechanism is still a hypothesized model without experimental evidence (105).