{"doi":"10.1128/jb.00703-17","title":"A Multimodal Strategy Used by a Large c-di-GMP Network","abstract":"The <i>Pseudomonas fluorescens</i> genome encodes more than 50 proteins predicted to be involved in c-di-GMP signaling. Here, we demonstrated that, tested across 188 nutrients, these enzymes and effectors appeared capable of impacting biofilm formation. Transcriptional analysis of network members across ∼50 nutrient conditions indicates that altered gene expression can explain a subset of but not all biofilm formation responses to the nutrients. Additional organization of the network is likely achieved through physical interaction, as determined via probing ∼2,000 interactions by bacterial two-hybrid assays. Our analysis revealed a multimodal regulatory strategy using combinations of ligand-mediated signals, protein-protein interaction, and/or transcriptional regulation to fine-tune c-di-GMP-mediated responses. These results create a profile of a large c-di-GMP network that is used to make important cellular decisions, opening the door to future model building and the ability to engineer this complex circuitry in other bacteria.<b>IMPORTANCE</b> Cyclic diguanylate (c-di-GMP) is a key signaling molecule regulating bacterial biofilm formation, and many microbes have up to dozens of proteins that make, break, or bind this dinucleotide. A major open issue in the field is how signaling specificity is conferred in the unpartitioned space of a bacterial cell. Here, we took a systems approach, using mutational analysis, transcriptional studies, and bacterial two-hybrid analysis to interrogate this network. We found that a majority of enzymes are capable of impacting biofilm formation in a context-dependent manner, and we revealed examples of two or more modes of regulation (i.e., transcriptional control with protein-protein interaction) being utilized to generate an observable impact on biofilm formation.","journal":"Journal of Bacteriology","year":2018,"id":1223,"datarank":1.8388285856793376,"base_score":4.219507705176107,"endowment":4.219507705176107,"self_citation_contribution":0.6329261557764161,"citation_network_contribution":1.2059024299029215,"self_endowment_contribution":0.6329261557764161,"citer_contribution":1.2059024299029215,"corpus_percentile":null,"corpus_rank":null,"citation_count":67,"citer_count":52,"citers_with_citation_signal":40,"citers_with_endowment":40,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2018-04-15","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":15817,"name":"Alan J. Collins","orcid":"0000-0003-4960-5716","position":1,"is_corresponding":false},{"id":454,"name":"Georgia Doing","orcid":"0000-0002-0835-6955","position":2,"is_corresponding":false},{"id":2967,"name":"Jaclyn N. Taroni","orcid":"0000-0003-4734-4508","position":3,"is_corresponding":false},{"id":15818,"name":"Timothy J. Gauvin","orcid":null,"position":4,"is_corresponding":false},{"id":308,"name":"Casey S. Greene","orcid":"0000-0001-8713-9213","position":5,"is_corresponding":false},{"id":456,"name":"Deborah A. Hogan","orcid":"0000-0002-6366-2971","position":6,"is_corresponding":false},{"id":15819,"name":"George A. O'Toole","orcid":"0000-0002-2861-4392","position":7,"is_corresponding":false},{"id":15816,"name":"Kurt M. Dahlstrom","orcid":"0000-0001-6590-6020","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}