Cyclic-di-GMP (c-di-GMP) is a ubiquitous second messenger in bacteria and regulates a variety of cell activities. Many bacteria contain a large number of enzymes involved in cyclic-di-GMP synthesis or degradation. However, how they coordinate with each other to orchestrate c-di-GMP homeostasis remains unclear.

Anabaena sp. PCC 7120 (Anabaena) is a filamentous cyanobacterium that houses 16 genes for c-di-GMP metabolism. Only one of them CdgS was identified as the primary diguanylate cyclase (DGC) responsible for cell size regulation. Therefore, potential compensatory or redundant functions of the remaining 15 c-di-GMP metabolic proteins in cell size control and other physiological processes need to be elucidated.

Recently, a research group led by Prof. Zhang Cheng-Cai from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences uncovered that the cell fate of a cyanobacterium is controlled by a dual-threshold system relying on multiple c-di-GMP metabolic enzymes. This study was published in PLOS Biology.

In this study, using the cyanobacterium Anabaena PCC 7120 as a model, the researchers created cdG0 and cdGmax strains by deleting all 8 and 14 genes, respectively, that encode enzymes with c-di-GMP degradation and synthesis domains. They also generated a collection of mutant deletion mutants with various numbers of these genes. The researchers demonstrate that c-di-GMP in Anabaena not only modulates cell size but is also indispensable for cell viability.

Quantitative analysis established two critical physiological thresholds in vivo: a minimal cyclic-di-GMP level (80%) required for cell size maintenance and a lower, lethal threshold (50%) essential for survival.

“By systematic analysis, we identify the dominant DGCs and phosphodiesterases (PDEs) in this cyanobacterium and propose that the c-di-GMP metabolic enzymes function in a manner that simulates an electromechanical dual relay system to control the c-di-GMP hemostasis.” said Prof. Zhang.

In this system, thirteen enzymes constitute a baseline signal power, two acting as a responsive relay, and one as an emergency relay that is activated only when c-di-GMP concentration drops to a lethal level.

These findings demonstrate how nature repurposes the conserved signaling molecule c-di-GMP to construct novel regulatory architectures adapted to specific environmental contexts. Beyond revealing novel adaptation strategies in cyanobacteria, this mechanism provides a blueprint for engineering synthetic biological systems that require multi-level regulation.

Cell size and cell fate regulation of a cyanobacterium (Image by IHB)

(Editor: MA Yun)