Abstract
Salmonella alters cellular processes as a strategy to improve its intracellular fitness during host infection. Alternative σ factors are known to rewire cellular transcriptional regulation in response to environmental stressors. σs factor encoded by the rpoS gene is a key regulator required for eliciting the general stress response in many proteobacteria. In this study, Salmonella Typhimurium deprived of an outer membrane protein YcfR was attenuated in intracellular survival and exhibited downregulation in Salmonella pathogenicity island-2 (SPI-2) genes. This decreased SPI-2 expression caused by the outer membrane perturbation was abolished in the absence of rpoS. Interestingly, regardless of the defects in the outer membrane integrity, RpoS overproduction decreased transcription from the common promoter of ssrA and ssrB, which encode a two-component regulatory system for SPI-2. RpoS was found to compete with RpoD for binding to the PssrA region, and its binding activity with RNA polymerase (RNAP) to form Eσs holoenzyme was stimulated by the small regulatory protein Crl. This study demonstrates that Salmonella undergoing RpoS-associated stress responses due to impaired envelope integrity may reciprocally downregulate the expression of SPI-2 genes to reduce its virulence.
Highlights
The bacterial RNA polymerase (RNAP) holoenzyme is a provisional complex between a multisubunit RNAP core enzyme (E, α2ββ'ω) and an σ factor
YcfR, which is expressed in response to multiple stress conditions, is a putative outer membrane protein important for stress resistance in enteric pathogens such as Salmonella spp. and E. coli (Zhang et al, 2007; Salazar et al, 2013)
In order to figure out a transcriptional regulator that coordinates bacterial virulence in response to outer membrane perturbation, we assessed the expression of 21 regulators associated with SPI-1 or Salmonella pathogenicity island-2 (SPI-2) regulation in the ΔycfR strain (Supplementary Figure 2) and found that rpoS showed a dramatic increase in its transcription
Summary
The bacterial RNA polymerase (RNAP) holoenzyme is a provisional complex between a multisubunit RNAP core enzyme (E, α2ββ'ω) and an σ factor. The σ factor forming the Eσ complex directs promoter-specific transcription initiation and dissociates from the core enzyme E after transcription initiation. Bacteria exploit alternative σ factors to redistribute RNAP core enzyme specificity toward discrete subsets of genes whose products help survive and adapt to environmental stressors (Bang et al, 2005). Different σ factors operate discrete regulatory circuits containing cognate genes and operons in response to specific environmental cues, but some transcriptional regulons are coordinated by multiple σ factors that function in a regulatory cascade or by competitive interactions. In response to the diverse stimuli encountered by bacterial pathogens upon host infection, multiple alternative σ factors interact with each other to promote bacterial adaptation in hostile conditions. Competitive binding of EσS to the overlapping promoter regions may occlude transcription initiation by Eσ70, inducing the transcription of a repertoire of genes by σS under stressful environments (Levi-Meyrueis et al, 2015)
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