Global Regulation by CsrA and Its RNA Antagonists

Abstract

The sequence-specific RNA binding protein CsrA is employed by diverse bacteria in the posttranscriptional regulation of gene expression. Its binding interactions with RNA have been documented at atomic resolution and shown to alter RNA secondary structure, RNA stability, translation, and/or Rho-mediated transcription termination through a growing number of molecular mechanisms. In Gammaproteobacteria, small regulatory RNAs (sRNAs) that contain multiple CsrA binding sites compete with mRNA for binding to CsrA, thereby sequestering and antagonizing this protein. Both the synthesis and turnover of these sRNAs are regulated, allowing CsrA activity to be rapidly and efficiently adjusted in response to nutritional conditions and stresses. Feedback loops between the Csr regulatory components improve the dynamics of signal response by the Csr system. The Csr system of Escherichia coli is intimately interconnected with other global regulatory systems, permitting it to contribute to regulation by those systems. In some species, a protein antagonist of CsrA functions as part of a checkpoint for flagellum biosynthesis. In other species, a protein antagonist participates in a mechanism in which a type III secretion system is used for sensing interactions with host cells. Recent transcriptomics studies reveal vast effects of CsrA on gene expression through direct binding to hundreds of mRNAs, and indirectly through its effects on the expression of dozens of transcription factors. CsrA binding to base-pairing sRNAs and novel mRNA segments, such as the 3' untranslated region and deep within coding regions, predict its participation in yet-to-be-discovered regulatory mechanisms.

FIGURE 1

(A) Example of a high-affinity CsrA binding site. The conserved GGA motif is in red. (B) Structure of the CsrA-RNA complex. The GGA motifs are indicated by blue boxes, and the critical L4 and R44 residues are indicated in red. Adapted from reference with permission.

FIGURE 2

Mechanisms for CsrA-mediated translational repression (A), transcription termination (B), and protection of mRNA from nuclease cleavage. Adapted from reference with permission.

FIGURE 3

Modes of CsrA antagonism. In various species, dedicated sRNAs, moonlighting sRNAs, mRNA, and/or proteins have been found to bind to CsrA and inhibit its activity.

FIGURE 4

Central regulatory circuitry of the Csr system. Dedicated components of the Csr system are highlighted in red.

FIGURE 5

Regulatory interactions of the Csr system with stringent response (A), extracytoplasmic stress (B), and carbon catabolite repression (C) global regulatory systems. Adapted from references , , and with permission.