The PqsE-RhlR Interaction Regulates RhlR DNA Binding to Control Virulence Factor Production in .

TitleThe PqsE-RhlR Interaction Regulates RhlR DNA Binding to Control Virulence Factor Production in .
Publication TypeJournal Article
Year of Publication2022
AuthorsSimanek, KA, Taylor, IR, Richael, EK, Lasek-Nesselquist, E, Bassler, BL, Paczkowski, JE
JournalMicrobiol Spectr
Volume10
Issue1
Paginatione0210821
Date Published2022 02 23
ISSN2165-0497
KeywordsAnti-Bacterial Agents, Bacterial Proteins, Cell Communication, DNA-Binding Proteins, Gene Expression Regulation, Bacterial, Humans, Pseudomonas aeruginosa, Quorum Sensing, Virulence, Virulence Factors
Abstract

<p>Pseudomonas aeruginosa is an opportunistic pathogen that causes disease in immunocompromised individuals and individuals with underlying pulmonary disorders. P. aeruginosa virulence is controlled by quorum sensing (QS), a bacterial cell-cell communication mechanism that underpins transitions between individual and group behaviors. In P. aeruginosa, the PqsE enzyme and the QS receptor RhlR directly interact to control the expression of genes involved in virulence. Here, we show that three surface-exposed arginine residues on PqsE comprise the site required for interaction with RhlR. We show that a noninteracting PqsE variant [PqsE(NI)] possesses catalytic activity, but is incapable of promoting virulence phenotypes, indicating that interaction with RhlR, and not catalysis, drives these PqsE-dependent behaviors. Biochemical characterization of the PqsE-RhlR interaction coupled with RNA-seq analyses demonstrates that the PqsE-RhlR complex increases the affinity of RhlR for DNA, enabling enhanced expression of genes encoding key virulence factors. These findings provide the mechanism for PqsE-dependent regulation of RhlR and identify a unique regulatory feature of P. aeruginosa QS and its connection to virulence. Bacteria use a cell-cell communication process called quorum sensing (QS) to orchestrate collective behaviors. QS relies on the group-wide detection of molecules called autoinducers (AI). QS is required for virulence in the human pathogen Pseudomonas aeruginosa, which can cause fatal infections in patients with underlying pulmonary disorders. In this study, we determine the molecular basis for the physical interaction between two virulence-driving QS components, PqsE and RhlR. We find that the ability of PqsE to bind RhlR correlates with virulence factor production. Since current antimicrobial therapies exacerbate the growing antibiotic resistance problem because they target bacterial growth, we suggest that the PqsE-RhlR interface discovered here represents a new candidate for targeting with small molecule inhibition. Therapeutics that disrupt the PqsE-RhlR interaction should suppress virulence. Targeting bacterial behaviors such as QS, rather than bacterial growth, represents an attractive alternative for exploration because such therapies could potentially minimize the development of resistance.</p>

DOI10.1128/spectrum.02108-21
Alternate JournalMicrobiol Spectr
PubMed ID35019777
PubMed Central IDPMC8754118
Grant ListF32 GM134583 / GM / NIGMS NIH HHS / United States
R37 GM065859 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute (HHMI) /