The Iron-Responsive Fur/RyhB Regulatory Cascade Modulates the Shigella Outer Membrane Protease IcsP

Abstract

Actin-based motility is central to the pathogenicity of the intracellular bacterial pathogen Shigella. Two Shigella outer membrane proteins, IcsA and IcsP, are required for efficient actin-based motility in the host cell cytoplasm, and the genes encoding both proteins are carried on the large virulence plasmid. IcsA triggers actin polymerization on the surface of the bacterium, leading to the formation of an actin tail that allows both intraand intercellular spread. IcsP, an outer membrane protease, modulates the amount and distribution of the IcsA protein on the bacterial surface through proteolytic cleavage of IcsA. Transcription of icsP is increased in the presence of VirB, a DNA-binding protein that positively regulates many genes carried on the large virulence plasmid. In Shigella dysenteriae, the small regulatory RNA RyhB, which is a member of the iron-responsive Fur regulon, suppresses several virulence-associated phenotypes by downregulating levels of virB in response to iron limitation. Here we show that the Fur/RyhB regulatory pathway downregulates IcsP levels in response to low iron concentrations in Shigella flexneri and that this occurs at the level of transcription through the RyhB-dependent regulation of VirB. These observations demonstrate that in Shigella species the Fur/RyhB regulatory pathway provides a mechanism to finely tune the expression of icsP in response to the low concentrations of free iron predicted to be encountered within colonic epithelial cells.

Ferric Uptake Regulator and Its Role in the Pathogenesis of Nontypeable Haemophilus influenzae

“…RhyB represses the expression of the regulator VirB. RhyB thus modulates expression of the VirB regulon, which is critical in Shigella pathogenesis (85,86). Shigella is possibly using RhyB, through Fur, to sense host iron and thus modulate in vivo expression of the VirB regulon.…”

Elemental Economy

“…For those organisms more closely related to E. coli , RyhB orthologs are common and a similar overall pathway is likely present. For example, RyhB orthologs have been described for Shigella (Africa et al, 2011) and Vibrio spp. (Davis et al, 2005, Mey et al, 2005).…”

The Small RNA RyhB Contributes to Siderophore Production and Virulence of Uropathogenic Escherichia coli

“…Thus, RyhB plays an essential role in bacteria that require adaptation to iron starvation. Moreover, this sRNA also contributes to many pathogenicity determinants, such as acid resistance in Shigella flexneri (21); eukaryotic cell invasion and cell-to-cell spread in Shigella dysenteriae (22,23); motility, chemotaxis, and biofilm formation in Vibrio cholerae (24,25); biosynthesis of capsular polysaccharide and iron acquisition in Klebsiella pneumoniae (26); and oxidative stress resistance, survival inside human macrophages, and iron acquisition in Salmonella enterica serovar Typhi (27).…”