The role of a LytS/LytTR-type histidine kinase/response regulator system in the stationary phase of Escherichia coli

• Applicant: Professorin Dr. Kirsten Jung
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432402323

LytS/LytTR-type histidine kinase/response regulator systems are widely distributed in Gram-positive and Gram-negative bacteria. These systems are important during infection of human and animal hosts as they somehow prevent premature cellular lysis and increase survival during antibiosis. Despite their important biological roles, almost nothing is known about the nature of the ligand received by the membrane-integrated LytS or the function of the target genes. Escherichia coli has two LytS/LytTR-type systems, the BtsS/BtsR and YpdA/YpdB systems. We have characterized the function of these two systems, and were the first to find that BtsS is a high-affinity sensor for extracellular pyruvate in E. coli, Salmonella and Vibrio species that, together with the response regulator BtsR, regulates the expression of a gene encoding a highly specific pyruvate transporter. The second system, the YpdA/YpdB system also responds to extracellular pyruvate, albeit with very low affinity. Serendipitously, we found a strong activation of the YpdA/YpdB-system in late stationary phase of E. coli, at a point which we now define as a turning point, at which cells decide to down-regulate metabolism and become persister or viable but nonculturable (VBNC) cells or die and lyse. Based on preliminary data we hypothesize that the LytS histidine kinase YdpA is a sensor for glyoxylate or oxaloacetate that, together with YpdB, activates the expression of yhjX, which encodes a putative oxaloacetate/malate antiporter that generates an electrical potential at low pH. In order to test these hypotheses, we will systematically investigate (1) the dynamics of the exometabolome, the transcriptome and the activity of distinct enzymes at different time points in the stationary phase of E. coli, (2) the ligand-YpdA interaction using biochemical methods, (3) the function of the transporter YhjX, and (4) the importance of YpdA/YpdB and YhjX for long-term survival at single cell level. By studying the importance of a signaling system and a transporter in the late stationary phase, we envision to uncover new targets for the treatment of chronic and recurrent bacterial infections.

• DFG Programme: Research Grants