Expanding the LuxR-type receptor functional repertoire: Protein-protein interactions in quorum sensing regulation.

Quorum sensing (QS) enables bacteria to coordinate gene expression in response to population density, with LuxR-type transcription factors playing a central role in this process for many Gram-negative species. Traditionally understood as ligand-activated transcriptional regulators, LuxR-type proteins are increasingly recognized as targets of diverse protein-protein interactions (PPIs) that modulate their activity, stability, and specificity. This review synthesizes emerging insights into the regulatory landscape of LuxR-type receptors, focusing on direct PPIs that expand the functional repertoire of LuxR-type receptors. We classify LuxR-interacting partners into negative regulators, dual or context-dependent regulators, and global regulators, highlighting the well-characterized system of PqsE-RhlR in Pseudomonas aeruginosa as well as emerging candidates. We discuss how these interactions influence LuxR-type receptor outputs beyond canonical ligand-mediated gene regulation, through stabilization of active conformations, inhibition of dimerization, proteolytic regulation, and potential recruitment of transcriptional machinery. By examining functional parallels, structural determinants, and environmental integration, we highlight a framework in which LuxR-type receptors are subject to diverse regulatory PPI that allow for the fine-tuning of QS output. Understanding these regulatory mechanisms offers promising alternatives to conventional QS disruption strategies, for targeted interference with bacterial virulence and communication.