Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS


cdGMP Berichtzusammenfassung

Project ID: 322809
Gefördert unter: FP7-IDEAS-ERC
Land: Switzerland

Mid-Term Report Summary - CDGMP (Time, space and speed: cdGMP signaling in cell behavior and reproduction.)

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 aims at establishing Caulobacter crescentus as a model for c-di-GMP mediated regulation of 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, chemotactic 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 chromosome replication and cell division. When challenged with surface, this developmental program is strongly accelerated leading to instantaneous surface attachment. Mechanosensation, 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 is to disclose how c-di-GMP orchestrates cellular processes promoting motility or sessility and how it firmly integrates these processes with the Caulobacter division cycle.
In the past 2-3 years we could show that oscillatory waves of c-di-GMP determine C. crescentus cell fate and drive the Caulobacter cell cycle. A systematic analysis of all known network components has identified a total of four diguanylate cyclases responsible for cell cycle oscillation of c-di-GMP and for rapid behavioral changes upon surface contact. To better understand their temporal and spatial control during the cell cycle we are currently identifying partner proteins mediating their subcellular localization, stability or activity. In parallel, we have pioneered Capture Compound Mass Spectrometry to identify and characterize a range of novel c-di-GMP effectors. This innovative and highly successful technique has paved the way into dissecting individual c-di-GMP dependent cellular processes and pathways in C. crescentus. This includes the identification of a novel family of c-di-GMP controlled CheY-like single domain response regulators (CheYcdG) that interact with the flagellar rotary motor in a c-di-GMP dependent manner to control motor function. We demonstrated that an active motor is required for mechanosensation and rapid surface attachment and that a subset of the CheYcdGs is involved in this process. Our primary goal is now to dissect the individual contribution of each of the CheYcdG proteins to motor control and surface recognition.
Finally, this project has identified a central role for c-di-GMP in the regulation of the Caulobacter cell cycle by uncovering bacterial sensor histidine kinases as important novel targets of c-di-GMP. We demonstrated that the cell cycle kinase CckA directly binds c-di-GMP and, in response, switches from its default kinase into phosphatase mode to initiate chromosome replication (Lori et al. 2015 Nature). Our next goal is to decipher the mechanistic details of c-di-GMP imposed activity control of this large and important class of bacterial regulatory enzymes.

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