Post-transcriptional global regulation by CsrA in bacteria

Abstract

Global regulation allows bacteria to rapidly modulate the expression of a large variety of unrelated genes in response to environmental changes. Global regulators act at different levels of gene expression. This review focuses on CsrA, a post-transcriptional regulator that affects translation of its gene targets by binding mRNAs. CsrA controls a large variety of physiological processes such as central carbon metabolism, motility and biofilm formation. The activity of CsrA is itself tightly regulated by the CsrB and CsrC small RNAs and the BarA-UvrY two-component system.

Fig. 1

Regulation of gene expression by global regulators. Different levels of gene expression regulation by global regulators are represented. Sigma factors, H-NS and cAMP control transcription. CsrA and sRNAs regulate translation by acting on mRNAs at the post-transcriptional level. Proteases and chaperones modulate stability and availability of functional protein at the post-translational level

Fig. 2

CsrA regulates numerous unrelated biological pathways. CsrA positively regulates glycolysis, acetate metabolism, mobility, pathogenesis, virulence, quorum sensing and oxidative stress response. It negatively controls biofilm formation, glycogenesis, gluconeogenesis and c-di-GMP synthesis, which is involved in the switch between planktonic and sessile life-styles

Fig. 3

Secondary structure of CsrA and RNA sequence and structure recognition. a CsrA is composed of five β-sheets (grey arrows) followed by an α-helix (black). The amino acid sequence of CsrA from E. coli is indicated. Domains involved in RNA recognition/binding based on the 3-D structure are shaded in grey [87] and on mutagenesis studies are boxed in black [55]. The KH domain is indicated in bold. Point of transposon insertion in the csrA::kan mutant is indicated by an arrow [44]. b The CsrA consensus recognition sequence is 5′-RUACARGGAUGU-3′ that is part of a stem-loop, the GGA motif being in the loop. CsrA is represented in grey

Fig. 4

CsrA regulates central carbon metabolism and glycogenesis. The pentose phosphate pathway, gluconeogenesis, glycolysis, glycogenesis and the Krebs cycle are indicated in grey. Genes whose expression is regulated by csrA are indicated (+ positive regulation, − negative regulation). The different steps of glycolysis, gluconeogenesis and glycogenesis are indicated. Since CsrA does not regulate the pentose phosphate pathway or the Krebs cycle, these pathways are not shown in detail (DHAP dihydroxyacetone-3-P, PEP phosphoenolpyruvate). Adapted from reference [80]

Fig. 5

Regulation of CsrA. The BarA-UvrY two-component system is activated by weak acids as well as Krebs cycle intermediates. This two-component system positively regulates expression of the sRNAs CsrB and CsrC. They sequester CsrA, thereby negatively controlling its activity. Expression of the sRNAs is negatively regulated by CsrD. In S. typhimurium and in E. coli, the CsrD homologue is negatively regulated by the CsrA homologue. CsrA also directly or indirectly regulates (via a putative X factor) the BarA-UvrY two-component system. Expression of UvrY is under the positive control of quorum sensing