Autoinducer-2 and bile salts induce c-di-GMP synthesis to repress the T3SS via the CesD/SycD/LcrH family of chaperones

Abstract

Abstract Cyclic di-GMP (c-di-GMP) is a bacterial second messenger that transduces extracellular stimuli into intracellular responses, efficiently coordinating a plethora of important biological processes. Low levels of c-di-GMP are often associated with highly virulent behavior that depends on the type III secretion system (T3SS) effectors encoded, whereas elevated levels of c-di-GMP lead to the repression of T3SSs. However, extracellular signals that modulate c-di-GMP metabolism to control T3SSs and the underlying mechanisms remain largely obscure. Here, we identify a GAPES1 domain-containing diguanylate cyclase (DGC) YeaJ that senses the quorum sensing signal autoinducer-2 (AI-2) to repress T3SS-1 gene expression in Salmonella enterica serovar Typhimurium. YeaJ homologs capable of sensing AI-2 are present in many other species belonging to Enterobacterales. We also reveal that bile components taurocholate and taurodeoxycholate bind to the periplasmic sensory domain of the DGC YedQ to induce intracellular accumulation of c-di-GMP, thus repressing the expression of T3SS-1 genes. Further, we found that c-di-GMP negatively controls the function of T3SSs through binding to the widely conserved CesD/SycD/LcrH family of T3SS chaperones. Our results support a model in which bacteria sense changes in population density and host-derived cues to regulate c-di-GMP synthesis, thereby modulating the activity of T3SSs via a c-di-GMP-responsive T3SS chaperone.