Interaction of the polar localization protein BscR with phosphodiesterase PipA regulates virulence strategies in Pseudomonas aeruginosa

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• BscR regulates biofilm formation, flagellum biosynthesis, and pyocyanin production in P. aeruginosa. • BscR localizes at the cell poles and modulates iron uptake. • BscR modulates biofilm formation and motility through PipA-dependent transcriptional control. • PipA disrupts BscR function by interfering with its polar localization in bacterial cells. • The polar localization of BscR depends on its interaction with CheB. • The regulatory proteins BscR and PipA exert control over pathogenic potential of P. aeruginosa. Bacteria synthesize cyclic diguanylate monophosphate (c-di-GMP) as a central second messenger to control multiple virulence-related phenotypes. In P. aeruginosa , while the major function of phosphodiesterases and diguanylate cyclases involves controlling cellular c-di-GMP concentrations, the exact pathways through which these enzymes mediate virulence expression are not fully understood. We aimed to identify interacting partners of phosphodiesterase PipA and elucidate their coordination with PipA in regulating bacterial virulence strategies. We employed co-immunoprecipitation and bacterial two-hybrid assays to identify BscR as an interacting partner of PipA. Our systematic investigation combining targeted gene disruption, phenotypic screening, and subcellular protein tracking revealed the regulatory network through which BscR and PipA govern bacterial virulence programs. Finally, we evaluated how BscR influences bacterial pathogenicity using cell infection and Galleria mellonella infection models. Our findings demonstrate that BscR deletion leads to significant reductions in biofilm formation and pyocyanin production, while enhancing bacterial motility. We further reveal that PipA modulates biofilm formation and motility through a BscR-dependent regulatory pathway. Notably, BscR and CheB exhibit co-localization at the cellular poles, with BscR’s polar localization requiring direct interaction with CheB. Importantly, we discovered that elevated PipA levels disrupt the BscR-CheB interaction, thereby attenuating BscR-mediated regulatory functions. Furthermore, BscR mutation significantly enhances bacterial virulence, as evidenced by increased cytotoxicity in A549 cell infection and Galleria mellonella infection assays. These findings elucidate that BscR in P. aeruginosa serves as a crucial regulatory factor in modulating bacterial virulence determinants. This study provides mechanistic insights into BscR-mediated virulence regulation, offering a framework to design innovative approaches targeting infection control.

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