A novel c-di-GMP signal system regulates biofilm formation in Pseudomonas aeruginosa

Abstract

The bacterial second messenger cyclic-di-GMP (c-di-GMP) controls biofilm formation and other phenotypes relevant to pathogenesis. The human pathogen Pseudomonas aeruginosa encodes 17 diguanylate cyclase (DGCs) proteins which are required for c-di-GMP synthesis. Therefore, the c-di-GMP regulatory system in P. aeruginosa is highly sophisticated. SiaD, one of the DGC enzymes, is co-transcribed with SiaA/B/C and has been shown to be essential for bacterial aggregate formation in response to environmental stress. However, the detailed function of this operon remains unknown. In our recent paper (Chen et al., doi: 10.15252/embj.2019103412), we have demonstrated that the siaABCD operon encodes a signaling network that regulates biofilm and aggregate formation by modulating the enzymatic activity of SiaD. Among this signaling system, SiaC interaction with SiaD promotes the diguanylate cyclase activity of SiaD and subsequently facilities the intracellular c-di-GMP synthesis; SiaB is a unique protein kinase that phosphorylates SiaC, whereas SiaA phosphatase can dephosphorylate SiaC. The phosphorylation state of SiaC is critical for its interaction with SiaD, which will switch on or off the DGC activity of SiaD. This report unveils a novel signaling system that controls biofilm formation, which may provide a potential target for developing antimicrobial drugs.

Keywords: Biofilm; Pseudomonas aeruginosa; SiaD; c-di-GMP.

Figure 1. FIGURE 1: Proposed model of the SiaA/B/C/D signaling network involved in regulation of biofilm and aggregate formation.

Under normal conditions (such as in rich media), the protein kinase SiaB dominates and maintains most SiaC molecules phosphorylated, which precludes the promotion of the DGC activity of SiaD. Under stress conditions (such as SDS exposure), SiaA phosphatase is activated and most SiaC remains dephosphorylated; in this situation, the dephosphorylated SiaC interacts with SiaD to stimulate the DGC activity of SiaD and subsequently produces sufficient c-di-GMP, which leads to the formation of aggregates and biofilms.