Chapter 14 : Csr (Rsm) System and Its Overlap and Interplay with Cyclic Di-GMP Regulatory Systems

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Free-living bacteria must respond rapidly to changing environmental and physiological conditions to survive stresses, maintain homeostasis and growth, and compete with other species. This chapter describes recent evidence of shared regulatory targets and interconnections between two global regulatory systems that antagonistically influence bacterial lifestyle choices by governing surface properties, biofilm development, motility, and in many species, virulence factors. The CsrD protein, which triggers the turnover of CsrB and CsrC RNAs by RNaseE, contains degenerate GGDEF and EAL domains but does not synthesize or degrade cyclic di-GMP (c-di-GMP). The chapter illustrates the interactions of Csr and its interplay with c-di-GMP global regulatory systems. Various features of the Csr (Rsm) system have been the subjects of previous reviews. BarA-UvrY homologs, which are present in many gram-negative bacteria, are variously known as Gac, Var, Exp, and Let two-component signal transduction system (TCS), and also work in conjunction with Csr systems. Importantly, the BarA-UvrY system also activates rpoS transcription in , possibly through DNA binding by the response regulator UvrY. Synthesis of c-di-GMP from two GTPs is catalyzed by diguanylate cyclases (DGC) that contain the GGDEF (DUF-1) domain. A recently discovered c-di-GMP binding element is not a protein but a riboswitch. This c-di-GMP binding RNA domain or aptamer was originally identified as a conserved GEMM sequence motif (genes for the environment, membranes, and motility) in the 5'-untranslated segment of numerous mRNAs involved in c-di-GMP metabolism, virulence, motility, and pilus formation.

Citation: Romeo T, Babitzke P. 2010. Csr (Rsm) System and Its Overlap and Interplay with Cyclic Di-GMP Regulatory Systems, p 201-214. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch14
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Image of Figure 1.
Figure 1.

Csr components and circuitry based on the system. (A) Ribbon diagram of the CsrA dimer. The two poly-peptides are interdigitated within the dimer. The first and fifth beta strands of opposite polypeptides (β-1 and β-5′; β-1’ and β-5) are parallel in the dimer. These parallel strands form two surfaces for RNA binding (one of which is circled), located on opposite sides of the protein ( ). (B) Predicted secondary structure and CsrA binding sites of CsrB RNA. The boldface and numbered GGA-containing sequences (most frequent, CAGGAUG) in the predicted loops or unstructured RNA, respectively, may serve as binding sites for CsrA ( ). The terminal stem-loop is a putative factor-independent terminator (Ter). nt, nucleotides. (C) Domain predictions for CsrD protein. TM, transmembrane; CC, coiled coil; PL, periplasmic loop; HAMP, HAMP-like domain; aa, amino acids. GGDEF and EAL domains are shown along with the noncanonical sequences in CsrD. The sequence ENQL at residues 581 to 584 is 100% conserved in apparent CsrD orthologs but is not present in other EAL domain proteins and is important for CsrD function ( ). (D) Wire diagram of Csr circuitry. X is an unknown regulator of BarA activity, which is regulated by CsrA ( ). BarA and UvrY are the two component signal transduction sensor kinase and response regulator, respectively, which activate and transcription ( ). SdiA is the homolog of LuxR, which responds to HSL and activates transcription ( ). RNase E and polynucleotide phospho-rylase (PNPase), are ribonucleases involved in CsrD-dependent decay of CsrB and CsrC ( ). Activation and repression are depicted using arrowheads and perpendicular lines, respectively. Two apparent autoregulatory loops are shown for CsrA (via SdiA and BarA) and one for UvrY (via BarA). Such regulation is evidence of tight and finely tuned control of CsrA activity within this circuitry.

Citation: Romeo T, Babitzke P. 2010. Csr (Rsm) System and Its Overlap and Interplay with Cyclic Di-GMP Regulatory Systems, p 201-214. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch14
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Image of Figure 2.
Figure 2.

Multitier repression of biofilm formation by CsrA. The regulatory circuitry by which Csr regulates or is posited to regulate biofilm formation at several levels in is shown. The binding of CsrA to the transcript leader at six sites represses translation of and destabilizes this transcript. This operon is needed for production, covalent modification, and secretion of the adhesive polysaccharide PGA ( ). CsrA binds specifically to transcripts for GGDEF proteins, including YdeH and YcdT, which synthesize c-di-GMP. Thus, CsrA represses levels of c-di-GMP in ( ). c-di-GMP somehow activates PGA production ( ). CsrA represses glycogen synthesis and turnover ( ), which also affects biofilm formation ( ). A possible biochemical pathway for this effect is shown, in which carbon flow into the synthesis of UDP-acetylglucosamine, the precursor of the adhesin PGA, is limited by CsrA repression of genes, by ( ), and perhaps, by regulation of the and genes ( ). Transcription of mRNA requires the NhaR LysR family DNA binding protein, which may represent another point of Csr regulation, based on the observation that the transcript copurifies with CsrA ( ). Conversely, CsrA activates motility by stabilizing mRNA ( ). OM, outer membrane; CM, cytoplasmic membrane.

Citation: Romeo T, Babitzke P. 2010. Csr (Rsm) System and Its Overlap and Interplay with Cyclic Di-GMP Regulatory Systems, p 201-214. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch14
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Image of Figure 3.
Figure 3.

Convergence of Csr and c-di-GMP regulation in CsrA and c-di-GMP have inverse effects on motility versus sessility. CsrA activates motility and represses biofilm formation, while c-di-GMP represses motility and activates biofilm formation. CsrA posttranscriptionally activates the master operon of the motility cascade, and is required for flagellum biosynthesis ( ), while it represses the structural genes for production, covalent modification, and secretion of the biofilm adhesin PGA ( ). CsrA represses genes for c-di-GMP biosynthesis ( ), including which is important for biofilm formation and PGA synthesis ( ). Because CsrA activates it should indirectly activate σ, the motility sigma factor that is under FlhDC control, and in turn should activate ( ), although this indirect effect was not apparent in array studies ( ). The latter gene encodes a c-di-GMP-specific PDE, which represses biofilm formation ( ). Because CsrA represses c-di-GMP production ( ), it might activate motility indirectly through effects on the PilZ domain protein, YcgR, although this remains to be seen. c-di-GMP activates expression of curli fimbriae ( ) and PGA production ( ) by undetermined mechanisms. Several feedback loops are apparent in this system: CsrA-BarA-UvrY-CsrB/C ( ), BarA-UvrY ( ), CsrA-CsrD-CsrB/C ( ), and NhaR, which activates its own transcription ( ) and that between CsrA and . In principle, may be regulated by CsrA through its effects on BarA-UvrY signaling ( ), which affects transcription ( ), or its effect on translation ( ), as Hfq functions as an RNA chaperone that mediates the positive effects of two antisense RNA regulators on translation ( ). In turn, σ has multiple regulatory effects on c-di-GMP and expression of genes for curli fimbriae ( ). The asterisk between σ and CsrA indicates conditional modest effects of on transcripts ( ). Not shown are the inverse effects of CsrA and σ on glycogen biosynthesis ( ). The question mark indicates that CsrA is predicted to repress translation ( ).

Citation: Romeo T, Babitzke P. 2010. Csr (Rsm) System and Its Overlap and Interplay with Cyclic Di-GMP Regulatory Systems, p 201-214. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch14
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