Bacterial cyclic di-GMP second-messenger signalling

A reusable bacterial intracellular second-messenger motif comprising GGDEF-mediated c-di-GMP synthesis, turnover by EAL or HD-GYP phosphodiesterases, and recognition by protein receptors. Synthesis and hydrolysis alter ligand availability, either in shared cellular pools or through local enzyme–effector interactions. The model samples Pseudomonadota, Bacillota and Spirochaetota; it does not imply that every bacterium has the motif, both phosphodiesterase classes or every receptor class. PilZ proteins and catalytically inactive GGDEF/EAL proteins provide distinct receptor implementations. Motility, adhesion, extracellular-polysaccharide production and host adaptation are receptor-specific outputs outside the core boundary.

Boundary: the required roles are synthesis, degradation and protein recognition of c-di-GMP. Receptor-dependent transcription, RNA effects, motility, adhesin retention and polysaccharide production remain downstream biology. Riboswitches and other protein receptor folds are outside this selected protein-receptor motif, not asserted absent. BdcA-associated DdpA is an optional, lineage-restricted regulatory part, not a universal cyclase subunit. Taxonomic sampling: the 17 reference proteins cover Pseudomonadota, Bacillota and Spirochaetota. Bacterial scope describes the distribution of this reusable motif, not universal genomic capacity. E. coli and B. subtilis provide EAL-only sampled turnover implementations; Borrelia provides EAL and HD-GYP enzymes. A panel spanning species must not be mistaken for a complete pathway in any one strain. The B. subtilis 168 reference proteins are distinguished from NCIB3610-derived experiments; Bordetella RB50 sequence records from strain 9.73 phenotypic work; and Borrelia B31 from derivative strains, as documented in member reviews. Family selectors are grounded in verified PANTHER classifications where available, with exact official labels and representative membership. Family membership is intersected with the stated activity; a PANTHER name containing phosphodiesterase does not make every member catalytic. PilZ receptors remain an explicitly functional grouping with a PilZ-domain requirement and demonstrated ligand binding; no unresolved PANTHER id is invented. No PAINT ancestral-node assertion is made from a domain match. Local versus global signalling: edges describe ligand supply or removal from a pool accessible to the specified receptor. They do not imply one homogeneous pool, direct regulatory binding between every cyclase and phosphodiesterase, or a universal receptor-affinity hierarchy. Evidence for local signalling requires more than a phenotype: direct interactions, pathway specificity and measurements of messenger levels must be considered together (PMID:37251514). Ontology: QuickGO checked on 2026-11-05 still defines GO:0061939 c-di-GMP signaling as transfer of information from one cell to another. The intracellular motif therefore retains c-di-GMP as its concept rather than importing that definition. This is an ontology issue to resolve, not evidence that the biological motif is absent. Retraction and catalytic scope: the retracted RpfG paper PMID:16611728 is not used to establish HD-GYP chemistry. PA4781 primary kinetics and Borrelia PdeB assays independently support turnover, with intermediate/product differences stated explicitly. Degenerate GGDEF/EAL receptors do not inherit cyclase/PDE activity from their domains. DdpA has an additional histidine-kinase region whose activity remains unresolved; its inactive GGDEF/EAL regions do not prove that kinase region is inactive.