{
  "abstract": "Background\n\nCyclic 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\n\nWe 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\n\nThis 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\n\nTogether, 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Oral Immunology and Infectious Diseases, University of Louisville, School of Dentistry, 501 S Preston Street, Rm355, Louisville, KY, 40202, USA.",
    "Department of Bioinformatics & Biostatistics, University of Louisville, School of Public Health and Information Sciences, Louisville, KY, USA.",
    "Emory Integrated Proteomics Core, Emory University, Atlanta, GA, USA.",
    "Department of Oral Immunology and Infectious Diseases, University of Louisville, School of Dentistry, 501 S Preston Street, Rm355, Louisville, KY, 40202, USA. fata.moradali@louisville.edu."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Suraj Adhikari"
    },
    {
      "affs": [
        0
      ],
      "name": "Shirin Ghods"
    },
    {
      "affs": [
        0
      ],
      "name": "Ratnam S Seelan"
    },
    {
      "affs": [
        0
      ],
      "name": "Masoud Hamidi"
    },
    {
      "affs": [
        1
      ],
      "name": "Michael Sekula"
    },
    {
      "affs": [
        2
      ],
      "name": "Pritha Bagchi"
    },
    {
      "affs": [
        0
      ],
      "name": "David A Scott"
    },
    {
      "affs": [
        0
      ],
      "name": "Richard J Lamont"
    },
    {
      "affs": [
        3
      ],
      "name": "Fata Moradali",
      "orcid": "0000-0002-0230-5006"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1g36p9xhtx9k4.bib",
  "cited_by": 0,
  "doi": "10.1186/s12964-026-03108-3",
  "fulltext_url": "https://europepmc.org/articles/PMC13700151",
  "id": "1g36p9xhtx9k4",
  "issns": [
    "1478-811X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42928305",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Bacterial Genetics and Biotechnology"
    ]
  ],
  "openalex": "W7171648523",
  "pdf_url": "https://europepmc.org/articles/PMC13700151?pdf=render",
  "pmcid": "PMC13700151",
  "pmid": "42928305",
  "published": "2026-07-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1g36p9xhtx9k4.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:20Z",
      "native_id": "MED:42928305",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42928305"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Bacterial Genetics and Biotechnology",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Rhythmic-phasic c-di-AMP signaling: a new paradigm for bacterial growth synchronization governed by a pseudo-phosphodiesterase and modifiable diadenylate cyclase.",
  "title_text": "Rhythmic-phasic c-di-AMP signaling: a new paradigm for bacterial growth synchronization governed by a pseudo-phosphodiesterase and modifiable diadenylate cyclase.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:20Z",
  "url": "https://research.draconitic.com/paper/1g36p9xhtx9k4",
  "venue": "Cell communication and signaling : CCS",
  "versions": []
}