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J Bacteriol 2017 Oct 17;199(22):e00475-17

Activation of Bvg-repressed genes in Bordetella pertussis by RisA requires cross-talk from a non co-operonic histidine kinase RisK.

Chen Q, Ng V, Warfel JM, Merkel TJ, Stibitz S


The two-component response regulator RisA, encoded by BP3554 in the Bordetella pertussis Tohama I genomic sequence, is a known activator of vrgs, a set of genes whose expression is increased under the same environmental conditions (known as modulation) that result in repression of the bvgAS virulence regulon. Here we demonstrate that RisA is phosphorylated in vivo and that RisA phosphorylation is required for activation of vrgs. An adjacent histidine kinase gene, risS, is truncated by frameshift mutation in B. pertussis, but not in B. bronchiseptica or B. parapertussis Neither deletion of risS' or bvgAS, nor phenotypic modulation with MgSO4, affected levels of RisA~P in B. pertussis However, RisA phosphorylation did require the histidine kinase encoded by BP3223, here named RisK (cognate histidine kinase of RisA). RisK was also required for expression of the vrgs. This requirement could be obviated by the introduction of the phosphorylation-mimicking RisAD60E mutant, indicating that an active conformation of RisA, but not phosphorylation per se, is crucial for vrg activation. Interestingly, expression of vrgs is still modulated by MgSO4 in cells harboring the RisAD60E mutation, suggesting that the activated RisA senses additional signals to control vrg expression in response to environmental stimuli. IMPORTANCE In B. pertussis, the BvgAS two-component system activates the expression of virulence genes by binding of BvgA~P to their promoters. Expression of the reciprocally-regulated vrgs requires RisA and is also repressed by the Bvg-activated BvgR. RisA is an OmpR-like response regulator, but RisA phosphorylation was not expected because the gene for its presumed, co-operonic, histidine kinase is inactivated by mutation. In this study, we demonstrate phosphorylation of RisA in vivo by a non co-operonic histidine kinase. We also show that RisA phosphorylation is necessary but not sufficient for vrg activation, but, importantly, is not affected by BvgAS status. Instead, we propose that vrg expression is controlled by BvgAS through its regulation of BvgR, a c-di-GMP phosphodiesterase.

Category: Journal Article
PubMed ID: #28827216 DOI: 10.1128/JB.00475-17
PubMed Central ID: #PMC5648863
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2017-08-27 Entry Last Modified: 2019-06-09