Cyclic di-GMP signalling and the regulation of bacterial virulence

Robert P Ryan

doi:10.1099/mic.0.068189-0

Abstract

Signal transduction pathways involving the second messenger cyclic di-GMP [bis-(3′-5′)-cyclic di-guanosine monophosphate] occur widely in bacteria where they act to link perception of environmental or intracellular cues and signals to specific alterations in cellular function. Such alterations can contribute to bacterial lifestyle transitions including biofilm formation and virulence. The cellular levels of the nucleotide are controlled through the opposing activities of diguanylate cyclases (DGCs) and phosphodiesterases (PDEs). The GGDEF domain of DGCs catalyses the synthesis of cyclic di-GMP from GTP, whereas EAL or HD-GYP domains in different classes of PDE catalyse cyclic di-GMP degradation to pGpG and GMP. We are now beginning to understand how alterations in cyclic di-GMP exert a regulatory action through binding to diverse receptors or effectors that include a small ‘adaptor’ protein domain called PilZ, transcription factors and riboswitches. The regulatory action of enzymically active cyclic di-GMP signalling proteins is, however, not restricted to an influence on the level of nucleotide. Here, I will discuss our recent findings that highlight the role that protein–protein interactions involving these signalling proteins have in regulating functions that contribute to bacterial virulence.

Highlights

Cyclic di-GMP [bis-(39-59)-cyclic di-guanosine monophosphate] was originally described in 1987 as an allosteric regulator of cellulose synthesis in Acetobacter xylinum ( Gluconacetobacter xylinus) (Fig. 1) (Ross et al, 1987)
My group’s findings from studies of the Rpf/DSF system in Xanthomonas campestris pv. campestris (Xcc) and their broader relevance to an understanding of regulation of virulence by cyclic di-GMP in other pathogens are discussed. This begins with a brief overview of the DSF signalling system in Xcc, before going on to review in more detail what is known of the multiple regulatory functions of RpfG and the HD-GYP domain, how such diverse regulatory actions are exerted and the bifunctional nature of certain GGDEF domain proteins
The evidence provided does not rule out the possibility that regulation of xag gene expression by Clp is more indirect, for example by positive regulation of a distinct repressor protein. These findings suggest that Clp links elevated levels of cyclic di-GMP to the altered expression of two factors that are known to influence biofilm formation

Summary

Introduction

Cyclic di-GMP [bis-(39-59)-cyclic di-guanosine monophosphate] was originally described in 1987 as an allosteric regulator of cellulose synthesis in Acetobacter xylinum ( Gluconacetobacter xylinus) (Fig. 1) (Ross et al, 1987). My group’s findings from studies of the Rpf/DSF system in Xcc and their broader relevance to an understanding of regulation of virulence by cyclic di-GMP in other pathogens are discussed This begins with a brief overview of the DSF signalling system in Xcc, before going on to review in more detail what is known of the multiple regulatory functions of RpfG and the HD-GYP domain, how such diverse regulatory actions are exerted and the bifunctional nature of certain GGDEF domain proteins. In this way DSF may act as a sensor for confinement and not just a monitor of the size of the population of producing cells

DSF perception and transduction via the twocomponent system RpfC and RpfG

Potential dual role of the DSF sensor kinase RpfC

Region of high sequence diversity

Extracellular enzyme synthesis Extracellular polysaccharide synthesis Motility

Regulation of biofilm formation

Concluding remarks and future questions