Strong cross-system interactions drive the activation of the QseB response regulator in the absence of its cognate sensor

Abstract

Significance Bacteria use regulatory modules called two-component systems to respond to changes in their surrounding environment. Bacteria have evolved ways to insulate each two-component system, thereby preventing unwanted cross-talk. Here we describe an example where partners of distinct two-component systems show remarkable cross-specificity for each other. Loss of the quorum-sensing Escherichia coli (Qse)BC sensor QseC leads to robust cross-interaction of its cognate partner QseB with the polymyxin resistance (Pmr)AB two-component system. This cross-interaction in the absence of the cognate sensor is detrimental, severely attenuating pathogen virulence. Our findings suggest that ( i ) robust cross-talk between noncognate partners is possible and ( ii ) this interaction can be manipulated for developing antivirulence strategies against uropathogenic E. coli and potentially other QseBC−PmrAB-bearing pathogens.

Transcriptional regulation of the Aggregatibacter actinomycetemcomitans ygiW–qseBC operon by QseB and integration host factor proteins

“…As expected, the primary phosphodonor for QseB is its cognate sensor, QseC, but interestingly QseB could be partially activated and induce transcription of ygiW-qseBC in the absence of QseC. The absence of QseC in E. coli results in constitutively high qseB transcription that arises from bidirectional crossregulation between the structurally related QseBC and PmrAB two-component systems (Guckes et al, 2013). Without QseC, the non-cognate PmrB kinase phosphorylated QseB and transcription of qseBC was also activated by PmrA resulting in constitutive expression of qseB.…”

“…Consistent with latter possibility, the genes that encode enzymes required for the production of acetylphosphate are present in the A. actinomycetemcomitans genome [D11S-1227 (pta) and D11S-1228 (ackA)]. Interestingly, the PmrAB two-component system of E. coli senses ferric iron and induces the expression of qseBC in response to this signal (Chen & Groisman, 2013;Guckes et al, 2013). In contrast, in the absence of PmrAB in A. actinomycetemcomitans, the induction of ygiW-qseBC expression in response to ferrous and ferric iron is dependent on QseBC itself, and appears to be similar to ferrous iron induction of H. influenzae ygiW-fisRS expression (Steele et al, 2012).…”

“…In UPEC, QseC has been reported to function as both a kinase and phosphatase activity that modulates QseB phosphorylation. This is important since QseB is also phosphorylated by the PmrB histidine kinase (Kostakioti et al, 2009;Guckes et al, 2013). Deletion of qseC in UPEC causes an aberrant upregulation and overactivation of QseB by PmrB, since QseB cannot be dephosphorylated in the mutant.…”

The Histidine Residue of QseC Is Required for Canonical Signaling between QseB and PmrB in Uropathogenic Escherichia coli

“…Studies in uropathogenic Escherichia coli (UPEC) investigating the basis of bacterial attenuation in the ΔqseC mutant uncovered that loss of QseC leads to a high abundance of phosphorylated response regulator (QseBϳP) that aberrantly regulates metabolic and virulence determinants (12,14). Subsequent studies identified that increased levels of QseBϳP in the qseC deletion mutant were due to the interaction of QseB with the PmrB sensor kinase of the PmrAB TCS (15). In vivo and biochemical studies demonstrated that PmrB could indiscriminately phosphorylate QseB at rates comparable to QseC and that deletion of the pmrB gene in the qseC deletion strain suppressed all the defective phenotypes associated with the absence of QseC (12,(14)(15)(16)(17).…”

The hierarchic network of metal-response transcription factors in Escherichia coli

“…103) QseC-QseB senses and binds not only the bacterial hormone-like AI (autoinducer)-3 signal but also the host epineprhine/norepineprhine hormones, 104) thereby inducing the flhDC operons coding for the master regulator of flagella and motility genes.…”