Final Report Summary - CDGMP (Time, space and speed: cdGMP signaling in cell behavior and reproduction.)
Small signaling molecules are optimally suited to orchestrate a rapid and global cellular response that allows bacteria to adjust their behavior in response to their changing environment. The second messenger cyclic di-GMP was recently discovered as one of the main regulators of bacterial growth, virulence and persistence offering novel and innovative ways to interfere with infections in humans. This ERC-sponsored project aimed at establishing Caulobacter crescentus as a model for c-di-GMP mediated regulation of bacterial cell growth and behavior and at exposing the molecular and conceptual framework for a rapidly growing research field of second messenger signaling in pathogenic and non-pathogenic bacteria. C. crescentus divides asymmetrically to produce a motile swarmer cell and a sessile, surface attached stalked cell, respectively. As part of its inherent life cycle, the swarmer progeny differentiates into a stalked cell and concurrently initiates cell proliferation. When swarmer cells encounter surfaces, this developmental program is strongly accelerated leading to instantaneous surface attachment. Tactile sensing, the ability to sensitively and rapidly respond to surfaces, is common to most bacteria and plays an important role in the initial encounter of pathogenic bacteria with their hosts. Our primary task was to disclose how c-di-GMP orchestrates cellular processes promoting motility or sessility on different time scales and how it firmly integrates these processes with the Caulobacter division cycle.
Our work has shown that oscillatory waves of c-di-GMP are responsible for Caulobacter cell cycle progression and cell fate determination. A systematic analysis has uncovered the network components responsible for the oscillation and asymmetric distribution of c-di-GMP during division. We have developed novel tools to identify proteins that bind c-di-GMP and we have determined how the activity of these proteins is regulated in time and space and how this in turn leads to the activation of individual cellular processes like motility, surface adherence or cell division. Key findings of our work include the discoveries that c-di-GMP directly interferes with phosphorylation networks by modulating the activity of core sensor histidine kinases; that bacteria can utilise their rotary flagellar motors as tactile sensors to rapidly increase c-di-GMP levels and induce surface adherence; and that the c-di-GMP network directly interferes with other small molecules like ppGpp to modulate cell growth and metabolism. Overall, this work established important regulatory paradigms and concepts that can be directly related to studies aiming at uncovering the role of c-di-GMP in less tractable but medically relevant human and animal pathogens.
Our work has shown that oscillatory waves of c-di-GMP are responsible for Caulobacter cell cycle progression and cell fate determination. A systematic analysis has uncovered the network components responsible for the oscillation and asymmetric distribution of c-di-GMP during division. We have developed novel tools to identify proteins that bind c-di-GMP and we have determined how the activity of these proteins is regulated in time and space and how this in turn leads to the activation of individual cellular processes like motility, surface adherence or cell division. Key findings of our work include the discoveries that c-di-GMP directly interferes with phosphorylation networks by modulating the activity of core sensor histidine kinases; that bacteria can utilise their rotary flagellar motors as tactile sensors to rapidly increase c-di-GMP levels and induce surface adherence; and that the c-di-GMP network directly interferes with other small molecules like ppGpp to modulate cell growth and metabolism. Overall, this work established important regulatory paradigms and concepts that can be directly related to studies aiming at uncovering the role of c-di-GMP in less tractable but medically relevant human and animal pathogens.