Control of virulence gene transcription by indirect readout in Vibrio cholerae and Salmonella enterica serovar Typhimurium

Abstract

SummaryIndirect readout mechanisms of transcription control rely on the recognition of DNA shape by transcription factors (TFs). TFs may also employ a direct readout mechanism that involves the reading of the base sequence in the DNA major groove at the binding site. TFs with winged helix–turn–helix (wHTH) motifs use an alpha helix to read the base sequence in the major groove while inserting a beta sheet ‘wing’ into the adjacent minor groove. Such wHTH proteins are important regulators of virulence gene transcription in many pathogens; they also control housekeeping genes. This article considers the cases of the non‐invasive Gram‐negative pathogen Vibrio cholerae and the invasive pathogen Salmonella enterica serovar Typhimurium. Both possess clusters of A + T‐rich horizontally acquired virulence genes that are silenced by the nucleoid‐associated protein H‐NS and regulated positively or negatively by wHTH TFs: for example, ToxR and LeuO in V. cholerae; HilA, LeuO, SlyA and OmpR in S. Typhimurium. Because of their relatively relaxed base sequence requirements for target recognition, indirect readout mechanisms have the potential to engage regulatory proteins with many more targets than might be the case using direct readout, making indirect readout an important, yet often ignored, contributor to the expression of pathogenic phenotypes.

Elucidating the Regulon of a Fur-like Protein in Mycobacterium avium subsp. paratuberculosis (MAP)

“…Binding locations were distributed almost evenly between intragenic and intergenic regions. While binding of Fur in intragenic regions refute the definition of a transcriptional factor (Browning and Busby, 2004), recent ChIP-seq studies with M. tuberculosis, E. coli, Salmonella, and Corynebacterium reported intragenic TF binding that play critical roles in transcription and significantly affect regulation of gene expression (Dillon et al, 2012;Fitzgerald et al, 2014;Knapp et al, 2015). Additionally, during characterization of the Fur regulon in Pseudomonas syringae, Butcher et al (2011) did not observe general differences between Fur binding to intergenic and intragenic sites.…”

Negative supercoiling of DNA by gyrase is inhibited in Salmonella enterica serovar Typhimurium during adaptation to acid stress

“…For example, DNA relaxation enhances the binding of the globally‐acting response regulator OmpR to its DNA targets, both in the core genome of Salmonella and in the SPI1 and SPI2 pathogenicity islands and this enhanced binding can be detected both in vivo and in vitro (Cameron and Dorman, ; Cameron et al ., ; Quinn et al ., ). OmpR makes very few base contacts with its A + T‐rich DNA targets, relying instead on interactions with the DNA phosphate backbone to achieve an indirect readout mechanism of gene regulation (Chakraborty et al ., ; Dorman and Dorman, ). These features are shared with many other DNA‐binding proteins that control the transcription of virulence genes in Salmonella and other pathogens (Dorman and Dorman, ).…”

“…The ompR gene is autoregulated and is critical for acid‐sensitive regulation of transcription (Bang et al ., ). It has a preference, both in vitro and in vivo , for binding to DNA targets that are relaxed rather than negatively supercoiled (Cameron et al ., ; Quinn et al ., ; Dorman and Dorman, ).…”

A Novel Legionella Genomic Island Encodes a Copper-Responsive Regulatory System and a Single Icm/Dot Effector Protein Transcriptionally Activated by Copper

“…All the direct regulators of EEGs described above (PmrA, CpxR, CsrA, Fis1, Fis3, and Fur) were found to be present in all the Legionella species examined (41,42), and they function as global regulators that regulate the expression of a large number of genes, including EEGs, scattered throughout the L. pneumophila genome (18)(19)(20)22). Besides global regulators, local regulators that regulate the expression of a small number of adjacent genes are also common in many bacterial systems (43,44), including pathogenesis-related genes in Vibrio cholerae and Salmonella enterica (45). Local regulators were shown to function as either activators or repressors, and in many cases, they are found in genomic islands together with the genes they regulate (46)(47)(48)(49).…”