Activation of the

Two-component systems represent a fundamental sense-response mechanism in bacterial cells and often play important roles in critical processes such as quorum sensing, antibiotic tolerance, and virulence. Much has been learned about the role/activity of response regulator proteins, and their impact on gene expression can be monitored using techniques such as RNAseq and ChIP-seq. In contrast, sensor histidine kinases (HKs) remain poorly understood. In most cases, neither the stimulating signal nor the precise mechanism of action is known. This is particularly true for intramembrane sensing HKs (IM-HKs), which sense signals within the bacterial cell membrane. In this study, we show that ScrA, a bacterially encoded transmembrane protein and potent activator of the SaeRS two-component system, interacts directly with the IM-HK SaeS. We demonstrate that the interaction occurs between the transmembrane domains of both proteins and identify three ScrA amino acid residues that are important for this interaction. These results demonstrate that accessory proteins can play an important role in modulating the activity of bacterial two-component systems. IMPORTANCE: Bacterial pathogens sense environmental stimuli to enable adaptation to new niches, with two-component systems (TCS) playing an important role in this process. TCS consist of a sensor protein that detects a specific signal (often a change in environment), and a response protein that carries out a cellular response (typically altering gene expression). The precise signals that activate TCS are poorly understood, but in general, they are thought to emanate from outside the bacterial cell. Here, we demonstrate that a small membrane protein produced by