Research in our lab is focused on the mechanisms that allow bacteria to control their own growth and reproduction. In particular, we try to understand how bacteria can dynamically adjust their growth rate and mode of proliferation in response to fluctuating environmental conditions, for example changes in nutrient availability or at the onset of environmental stress. As our primary model organism we use the fresh water bacterium Caulobacter crescentus, which divides asymmetrically and has well-defined cell cycle phases. In addition, we do some of our work in Escherichia coli and Salmonella enterica to study how the C. crescentus cell cycle circuit relates to the one of other bacteria, and to investigate how precise regulation of cell cycle progression contributes to bacterial persistence and pathogenesis. Our research can be divided into the following subareas:
Regulation of bacterial DNA replication by environmental cues
One of the key events in the cell cycle of all organisms is the initiation of DNA replication. In all bacteria it depends on the conserved replication initiator DnaA. Our recent work in C. crescentus revealed that the environmental control of DNA replication depends on precisely regulated production and degradation rates of DnaA. While conditions inducing unfolded protein stress stimulate DnaA proteolysis by the protease Lon (Jonas et al. 2013), nutrient depletion leads to a reduced rate of DnaA synthesis by a post-transcriptional mechanism involving the 5′ untranslated region of the dnaA transcript (Leslie et al. 2015). We are currently dissecting the precise molecular mechanisms underlying the post-transcriptional and proteolytic control of DnaA. We also compare the mechanisms of DNA replication control in C. crescentus with the ones used by E. coli and other bacteria.
Chaperones and cell cycle control
Previous work suggests that the regulation of bacterial growth and cell cycle progression is tightly connected with chaperone networks (Jonas et al. 2014). Chaperones have well-documented functions in maintaining protein homeostasis, but they can also have specific regulatory roles in diverse cellular processes by affecting the conformation, stability and function of protein substrates. In bacteria, the major molecular chaperones include the DnaK (Hsp70) and GroEL (Hsp60) systems. It has long been observed that mutants in dnaK or groEL display defects in DNA replication, chromosome segregation and cell division in various bacteria. However, these phenotypes remain poorly understood on the molecular level. We aim to unravel the precise cellular mechanisms by which DnaK and GroEL are connected with cell cycle and growth control in the model bacterium Caulobacter crescentus and how these connections ensure bacterial survival in changing environments.
Bacterial filamentation as a stress response
Various bacteria transform into filamentous cells under different stress conditions (Heinrich et al. 2015). Bacterial filamentation is the anomalous growth of bacteria, in which cells continue to elongate and replicate their DNA but do not divide. Stress-induced filamentous growth has been observed in diverse bacteria in nature and has been suggested to play a range of roles, from stress and antibiotic resistance to avoiding phagocytosis. Nevertheless, the molecular basis underlying this conspicuous morphological transformation remains in most cases poorly understood. Our on-going work aims to elucidate the mechanisms triggering bacterial filamentation in response to environmental cues and to investigate its physiological relevance.