Vibrio cholerae’sToxRS Bile Sensing System

Abstract

Cholera represents a diarrheal disease caused by the Gram-negative bacteriumVibrio cholerae. Its environmental persistence causing recurring sudden outbreaks is enabled byV. cholerae'srapid adaption to changing environments involving sensory proteins like ToxR and ToxS. Located at the inner membrane, ToxR and ToxS react to environmental stimuli like bile acid, thereby inducing survival strategies e.g. bile resistance and virulence regulation. Currently, transcription factor ToxR is described as main environmental sensor for bile acid, whose activity is enhanced by binding to ToxS. Here, the presented crystal structure of the sensory domains of ToxR and ToxS in combination with multiple bile acid interaction studies, reveals that a bile binding pocket of ToxS is only properly folded upon binding to ToxR. These findings support the previously suggested link between ToxRS and VtrAC-like co-component systems. Besides VtrAC, ToxRS is now the only experimentally determined structure within this recently defined superfamily, further emphasizing its significance. In-depth analysis of the ToxRS complex reveals its remarkable conservation across variousVibriospecies, underlining the significance of conserved residues in the ToxS barrel and the more diverse ToxR sensory domain. Unraveling the intricate mechanisms governing ToxRS's environmental sensing capabilities, provides a promising tool for disruption of this vital interaction, ultimately inhibitingVibrio'ssurvival and virulence. Our findings hold far-reaching implications for allVibriostrains that rely on the ToxRS system as a shared sensory cornerstone for adapting to their surroundings.