Think globally, act locally: how bacteria integrate local decisions with their global cellular programme.

It has long been speculated that the bacterial second messenger c-di-GMP, a key molecular switch of bacterial community behaviour and persistence, can trigger specific cellular processes both on a global level as well as through some local action that prevents crosstalk originating from rapid diffusion of the signalling molecule. In this issue, Lindenberg et al (2013) report on a mechanism that not only helps to explain how spatial sequestration of c-diGMP signalling components could be organized within bacterial cells, but also demonstrates how global and local command levels are interconnected. One of the fundamental changes in behaviour of bacterial cells, the switch from motile single cells to surface grown sessile communities called biofilms, is regulated by the second messenger c-di-GMP. C-di-GMP is widespread in the bacterial world influencing different cellular processes on the transcriptional, translational and post-translational level (Hengge, 2009). Synthesis and degradation of c-diGMP are catalysed by GGDEF domain diguanylate cyclases (DGCs) and by EAL or HD-GYP domain phosphodiesterases (PDEs), respectively (Schirmer and Jenal, 2009). Differential cellular concentrations of c-di-GMP resulting from the regulated activities of DGCs and PDEs are converted into specific readouts by a range of effector proteins and RNAs. Most bacteria encode more than one member of the GGDEF and EAL/HD-GYP domain families and many organisms contain a multitude of these components. This observation raised the question if multiple DGCs and PDEs contribute to a common cellular pool and thus converge into co-regulating related cellular processes or if there is functional sequestration that allows the cell to activate distinct processes in parallel without significant crosstalk. Such functional sequestration was predicted in several bacteria by genetic studies demonstrating that individual DGCs or PDEs target distinct c-di-GMP-dependent processes. In general, two different regulatory scenarios can explain c-di-GMP signalling specificity. Serial activation of DGCs could lead to a graded response regulating a series of downstream effectors in a defined order, which is dictated primarily by the allosteric inhibition constants of the DGCs and by the binding affinities of the effector molecules (Christen et al, 2006; Pultz et al, 2012). Although still serving a common c-di-GMP pool, in such a setting DGCs would have kinetic specificity for a given readout. As an alternative, it was proposed that signalling specificity involves some local organization of DGCs and/or PDEs generating separate pools of c-di-GMP. Evidence in favour of spatial sequestration comes from examples demonstrating that DGCs and PDEs can directly interact with each other and that they can localize to specific subcellular sites (Abel et al, 2011; Tuckerman et al, 2011). Despite of rapid diffusion of