MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR‐class regulatory protein, has dual ligands

Abstract

SummaryMvfR (PqsR), a Pseudomonas aeruginosa LysR-type transcriptional regulator, plays a critical role in the virulence of this pathogen. MvfR modulates the expression of multiple quorum sensing (QS)-regulated virulence factors; and the expression of the phnAB and pqsA-E genes that encode functions mediating 4-hydroxy-2-alkylquinolines (HAQs) signalling compounds biosynthesis, including 3,4-dihydroxy-2-heptylquinoline (PQS) and its precursor 4-hydroxy-2-heptylquinoline (HHQ). PQS enhances the in vitro DNA-binding affinity of MvfR to the pqsA-E promoter, to suggest it might function as the in vivo MvfR ligand. Here we identify a novel MvfR ligand, as we show that HHQ binds to the MvfR ligand-binding-domain and potentiates MvfR binding to the pqsA-E promoter leading to transcriptional activation of pqsA-E genes. We show that HHQ is highly produced in vivo, where it is not fully converted into PQS, and demonstrate that it is required for MvfR-dependent gene expression and pathogenicity; PQS is fully dispensable, as pqsHmutant cells, which produce HHQ but completely lack PQS, display normal MvfR-dependent gene expression and virulence. Conversely, PQS is required for full production of pyocyanin. These results uncover a novel biological role for HHQ; and provide novel insights on MvfR activation that may aid in the development of therapies that prevent or treat P. aeruginosa infections in humans.

Quorum sensing in bacterial virulence

“…PqsR is a LysR transcriptional factor that is activated by HHQ and PQS, leading to the positive activation of many virulence factors, which include a large number of genes also controlled by las and rhl. In addition, PqsR also controls the pqs operon itself, generating a positive feedback loop (Cao et al, 2001;Déziel et al, 2004Déziel et al, , 2005Xiao et al, 2006). Interestingly, the expression of PqsR is positively regulated by the las system (Xiao et al, 2006).…”

“…In addition, PqsR also controls the pqs operon itself, generating a positive feedback loop (Cao et al, 2001;Déziel et al, 2004Déziel et al, , 2005Xiao et al, 2006). Interestingly, the expression of PqsR is positively regulated by the las system (Xiao et al, 2006). RlhR, in turn, affects the expression of the pqs system (Hazan et al, 2010;McGrath et al, 2004;Xiao et al, 2006).…”

“…Interestingly, the expression of PqsR is positively regulated by the las system (Xiao et al, 2006). RlhR, in turn, affects the expression of the pqs system (Hazan et al, 2010;McGrath et al, 2004;Xiao et al, 2006). Through transcriptome analysis, over 90 genes were found to be regulated by the pqs system (Bredenbruch et al, 2006;Déziel et al, 2005).…”

Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

“…Upon binding to its cognate signal molecule, LasR or RhlR activates the transcription of target genes (35). P. aeruginosa QS is also regulated by another system, which involves potentiation of transcriptional activation by MvfR (also known as PqsR) upon binding of a Pseudomonas quinolone signal (PQS) (55). The PQS/MvfR complex actively participates in the intertwined P. aeruginosa QS network, and accumulating evidence now suggests that PQS-mediated QS is absolutely required for the uninterrupted production of elastase (29,36).…”

Pseudomonas Quinolone Signal Affects Membrane Vesicle Production in not only Gram-Negative but also Gram-Positive Bacteria

“…The transcription of pqsABCDE operon is positively regulated by PqsR, whose ligands are HHQ and PQS (5). The conversion of HHQ into PQS is mediated by PqsH (5,41). Although pqsR and pqsH are specific to P. aeruginosa, the pqsABCDE operon is conserved in many Pseudomonas and Burkholderia species (7,39).…”