Although two-component systems are a ubiquitous means of rapid bacterial adaptation to changing environments, identification of the specific signals detected by sensor kinases can be challenging. Also, little is known about the diverse, poorly characterized family of sensor kinases that detect intramembrane signals. We show that the major type IV pilin, PilA, is an inhibitory intramembrane ligand for the PilS sensor kinase that controls
pilAexpression and we characterize the mechanism of signal transduction. Because the conserved N-terminal domain of PilA alone can repress pilAexpression, peptides corresponding to this short region could have potential as therapeutic agents to suppress type IV Pili (T4P) biogenesis.