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<i>Vibrio cholerae</i> controls the pathogenicity of interactions with arthropod hosts via the activity of the CrbS/R two-component system. This signaling pathway regulates the consumption of acetate, which in turn alters the relative virulence of interactions with arthropods, including <i>Drosophila melanogaster</i> CrbS is a histidine kinase that links a transporter-like domain to its signaling apparatus via putative STAC and PAS domains. CrbS and its cognate response regulator are required for the expression of acetyl coenzyme A (acetyl-CoA) synthetase (product of <i>acs</i>), which converts acetate to acetyl-CoA. We demonstrate that the STAC domain of CrbS is required for signaling in culture; without it, <i>acs</i> transcription is reduced in LB medium, and <i>V. cholerae</i> cannot grow on acetate minimal media. However, the strain remains virulent toward <i>Drosophila</i> and expresses <i>acs</i> similarly to the wild type during infection. This suggests that there is a unique signal or environmental variable that modulates CrbS in the gastrointestinal tract of <i>Drosophila</i> Second, we present evidence in support of CrbR, the response regulator that interacts with CrbS, binding directly to the <i>acs</i> promoter, and we identify a region of the promoter that CrbR may target. We further demonstrate that nutrient signals, together with the cAMP receptor protein (CRP)-cAMP system, control <i>acs</i> transcription, but regulation may occur indirectly, as CRP-cAMP activates the expression of the <i>crbS</i> and <i>crbR</i> genes. Finally, we define the role of the Pta-AckA system in <i>V. cholerae</i> and identify redundancy built into acetate excretion pathways in this pathogen.<b>IMPORTANCE</b> CrbS is a member of a unique family of sensor histidine kinases, as its structure suggests that it may link signaling to the transport of a molecule. However, mechanisms through which CrbS senses and communicates information about the outside world are unknown. In the <i>Vibrionaceae</i>, orthologs of CrbS regulate acetate metabolism, which can, in turn, affect interactions with host organisms. Here, we situate CrbS within a larger regulatory framework, demonstrating that <i>crbS</i> is regulated by nutrient-sensing systems. Furthermore, CrbS domains may play various roles in signaling during infection and growth in culture, suggesting a unique mechanism of host recognition. Finally, we define the roles of additional pathways in acetate flux, as a foundation for further studies of this metabolic nexus point.