Abstract
LeuO plays the role of a master regulator in the cyclic-L-phenylalanine-L-proline (cFP)-dependent signaling pathway in Vibrio vulnificus. cFP, as shown through isothermal titration calorimetry analysis, binds specifically to the periplasmic domain of ToxR. Binding of cFP triggers a change in the cytoplasmic domain of ToxR, which then activates transcription of leuO encoding a LysR-type regulator. LeuO binds to the region upstream of its own coding sequence, inhibiting its own transcription and maintaining a controlled level of expression. A five-bp deletion in this region abolished expression of LeuO, but a ten-bp deletion did not, suggesting that a DNA bending mechanism is involved in the regulation. Furthermore, binding of RNA polymerase was significantly lower both in the deletion of the ToxR binding site and in the five-bp deletion, but not in the ten-bp deletion, as shown in pull-down assays using an antibody against RNA polymerase subunit α. In summary, multiple factors are involved in control of the expression of LeuO, a master regulator that orchestrates downstream regulators to modulate factors required for survival and pathogenicity of the pathogen.
Highlights
IntroductionIt is an opportunistic human pathogen that causes septicemia and leads to high mortality[1]
Vibrio vulnificus is a gram negative, motile, curved bacterium[1]
Given the fact that LeuO, vHUα and vHUβ, and RpoS are each responsible for the regulation of separate regulons, and that many of the target genes are associated with pathogenicity, it is clear that LeuO is a key regulatory component of the cFP-signaling network, as is the case for the human pathogen V. cholerae
Summary
It is an opportunistic human pathogen that causes septicemia and leads to high mortality[1] This pathogenic Vibrio species produces a diketopiperazine (DKP) compound called cyclic-phenylalanine proline (cFP), that reaches maximum levels when cells enter stationary phase and triggers the expression of a series of genes associated with pathogenicity[2]. CFP inhibits interferon (IFN)-β production by inducing a conformational change in retinoic-acid-inducible gene-I (RIG-I)[10], affects innate immune responses[11], and causes apoptosis of human cell lines by elevating intracellular levels of reactive oxygen species (ROS)[12] These results suggest that cFP is a signaling molecule and a virulence factor. This study identified elements responsible for the regulation of LeuO in the human pathogen V. vulnificus, pointing to its role as a master regulator for the cFP-dependent signaling pathway and elucidating the underlying mechanisms for these elements, highlighting the complexity and importance of this pathway
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