Rhythmic-phasic c-di-AMP signaling: a new paradigm for bacterial growth synchronization governed by a pseudo-phosphodiesterase and modifiable diadenylate cyclase.
4 affiliations
- 1Department of Oral Immunology and Infectious Diseases, University of Louisville, School of Dentistry, 501 S Preston Street, Rm355, Louisville, KY, 40202, USA.
- 2Department of Bioinformatics & Biostatistics, University of Louisville, School of Public Health and Information Sciences, Louisville, KY, USA.
- 3Emory Integrated Proteomics Core, Emory University, Atlanta, GA, USA.
- 4Department of Oral Immunology and Infectious Diseases, University of Louisville, School of Dentistry, 501 S Preston Street, Rm355, Louisville, KY, 40202, USA. [email protected].
Abstract
Background
Cyclic di-adenosine monophosphate (c-di-AMP) is an essential bacterial second messenger that regulates bacterial physiology, survival, and pathogenesis. While current models describe c-di-AMP regulation as a linear synthesis-degradation paradigm through opposing activities of diadenylate cyclases (DACs) and c-di-AMP-specific phosphodiesterases (PDEs), they fail to capture the temporal complexity of c-di-AMP signaling dynamics in coordination with discrete growth-phase transitions, metabolic state, and redox homeostasis. In Porphyromonas gingivalis, a key Gram-negative proteolytic oral pathobiont relevant to oral and systemic disease, measurable canonical c-di-AMP degradation is absent, suggesting that c-di-AMP signaling operates through an atypical regulatory architecture mediated by the atypical phosphodiesterase PDEPg. Here, we identify rhythmic-phasic c-di-AMP signaling scheme in which PDEPg plays a critical role by coordinating with bacterial growth phase, metabolism, and cell cycle progression.Methods
We employed an integrated experimental and structural modeling framework that combined bacterial genetics, growth-phase-resolved nucleotide profiling, whole membrane fraction biochemical assays, untargeted metabolomics, transcriptomics, proteomics, post-translational modification profiling, ultrastructural transmission electron microscopy, structural modeling, and molecular dynamics simulations to dissect the pseudoenzymatic-controlled c-di-AMP regulatory module in P. gingivalis.Results
This study demonstrates that growth phase synchronization in P. gingivalis requires rhythmic-phasic c-di-AMP signaling, characterized by coordinated depletion-replenishment episodes of intracellular c-di-AMP during growth-phase transitions. This regulatory network is orchestrated by two key components: the atypical HD-domain PDE homolog, PDEPg, and the conserved serine residue (Ser-226) within the DACPg SEE loop. PDEPg maintains c-di-AMP homeostasis through a noncanonical regulatory mechanism rather than through measurable PDE-mediated hydrolysis. Disruption of PDEPg profoundly remodels bacterial physiology, resulting in altered c-di-AMP dynamics, impaired peptide-dependent metabolic adaptation, disrupted ATP homeostasis, and widespread post-translational remodeling, including condition-specific phosphorylation of the c-di-AMP cyclase DACPg at the conserved Ser226 residue. Functional genetic analyses demonstrate that Ser226 is required for proper coordination of rhythmic-phasic c-di-AMP signaling and metabolic adaptation, while pantothenate-mediated rescue further supports the contribution of metabolic homeostasis to these processes. Along with structural modeling and molecular dynamics simulations, these findings support a model in which noncanonical regulatory protein (pseudoenzymatic function) PDEPg coordinates rhythmic-phasic c-di-AMP signaling and physiological adaptation in P. gingivalis.Conclusion
Together, our findings establish a new paradigm in bacterial second messenger signaling, showing that pseudoenzymatic scaffolds coordinate rhythmic c-di-AMP dynamics that synchronize nutrient acquisition, redox metabolism, and cell-cycle progression, with broad implications for microbial physiology and pathogenesis.
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BibTeX
@article{adhikari2026rhythmicphasic,
title = {{Rhythmic-phasic c-di-AMP signaling: a new paradigm for bacterial growth synchronization governed by a pseudo-phosphodiesterase and modifiable diadenylate cyclase.}},
author = {Suraj Adhikari and Shirin Ghods and Ratnam S Seelan and Masoud Hamidi and Michael Sekula and Pritha Bagchi and David A Scott and Richard J Lamont and Fata Moradali},
journal = {Cell communication and signaling : CCS},
year = {2026},
month = jul,
doi = {10.1186/s12964-026-03108-3},
url = {https://europepmc.org/article/MED/42928305},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Rhythmic-phasic c-di-AMP signaling: a new paradigm for bacterial growth synchronization governed by a pseudo-phosphodiesterase and modifiable diadenylate cyclase.
AU - Suraj Adhikari
AU - Shirin Ghods
AU - Ratnam S Seelan
AU - Masoud Hamidi
AU - Michael Sekula
AU - Pritha Bagchi
AU - David A Scott
AU - Richard J Lamont
AU - Fata Moradali
PY - 2026
DA - 2026/07/29
JO - Cell communication and signaling : CCS
DO - 10.1186/s12964-026-03108-3
UR - https://europepmc.org/article/MED/42928305
AB - Background Cyclic di-adenosine monophosphate (c-di-AMP) is an essential bacterial second messenger that regulates bacterial physiology, survival, and pathogenesis. While current models describe c-di-AMP regulation as a linear synthesis-degradation paradigm through opposing activities of diadenylate cyclases (DACs) and c-di-AMP-specific phosphodiesterases (PDEs), they fail to capture the temporal complexity of c-di-AMP signaling dynamics in coordination with discrete growth-phase transitions, metabolic state, and redox homeostasis. In Porphyromonas gingivalis, a key Gram-negative proteolytic oral pathobiont relevant to oral and systemic disease, measurable canonical c-di-AMP degradation is absent, suggesting that c-di-AMP signaling operates through an atypical regulatory architecture mediated by the atypical phosphodiesterase PDEPg. Here, we identify rhythmic-phasic c-di-AMP signaling scheme in which PDEPg plays a critical role by coordinating with bacterial growth phase, metabolism, and cell cycle progression.Methods We employed an integrated experimental and structural modeling framework that combined bacterial genetics, growth-phase-resolved nucleotide profiling, whole membrane fraction biochemical assays, untargeted metabolomics, transcriptomics, proteomics, post-translational modification profiling, ultrastructural transmission electron microscopy, structural modeling, and molecular dynamics simulations to dissect the pseudoenzymatic-controlled c-di-AMP regulatory module in P. gingivalis.Results This study demonstrates that growth phase synchronization in P. gingivalis requires rhythmic-phasic c-di-AMP signaling, characterized by coordinated depletion-replenishment episodes of intracellular c-di-AMP during growth-phase transitions. This regulatory network is orchestrated by two key components: the atypical HD-domain PDE homolog, PDEPg, and the conserved serine residue (Ser-226) within the DACPg SEE loop. PDEPg maintains c-di-AMP homeostasis through a noncanonical regulatory mechanism rather than through measurable PDE-mediated hydrolysis. Disruption of PDEPg profoundly remodels bacterial physiology, resulting in altered c-di-AMP dynamics, impaired peptide-dependent metabolic adaptation, disrupted ATP homeostasis, and widespread post-translational remodeling, including condition-specific phosphorylation of the c-di-AMP cyclase DACPg at the conserved Ser226 residue. Functional genetic analyses demonstrate that Ser226 is required for proper coordination of rhythmic-phasic c-di-AMP signaling and metabolic adaptation, while pantothenate-mediated rescue further supports the contribution of metabolic homeostasis to these processes. Along with structural modeling and molecular dynamics simulations, these findings support a model in which noncanonical regulatory protein (pseudoenzymatic function) PDEPg coordinates rhythmic-phasic c-di-AMP signaling and physiological adaptation in P. gingivalis.Conclusion Together, our findings establish a new paradigm in bacterial second messenger signaling, showing that pseudoenzymatic scaffolds coordinate rhythmic c-di-AMP dynamics that synchronize nutrient acquisition, redox metabolism, and cell-cycle progression, with broad implications for microbial physiology and pathogenesis.
SN - 1478-811X
ER -