{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:23:05Z","timestamp":1792581785963,"version":"4.5.0"},"reference-count":52,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp;amp; Bioengineering"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Granulation is a complex microbial\u2010aggregation process essential for forming aerobic granular sludge (AGS) and other microbial granules used in wastewater treatment. However, the biological mechanisms that drive granule formation remain poorly understood. Cyclic\u2010di\u2010GMP (c\u2010di\u2010GMP) is a well\u2010established second messenger that regulates biofilm formation, suggesting it may be used to enhance microbial granulation.\n                    <jats:italic>Mycobacterium smegmatis<\/jats:italic>\n                    mc\n                    <jats:sup>2<\/jats:sup>\n                    155, a nonpathogenic model bacterium for\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    , naturally forms granules. Unlike other bacteria,\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    carries a single c\u2010di\u2010GMP modulating gene,\n                    <jats:italic>dcpA<\/jats:italic>\n                    , that encodes an enzyme with both diguanylate cyclase (DGC) and phosphodiesterase (PDE) activities; this genetic simplicity offers a unique opportunity to examine the role of c\u2010di\u2010GMP in granulation. Here, we generated and studied three engineered\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    strains overexpressing\n                    <jats:italic>dcpA<\/jats:italic>\n                    ,\n                    <jats:italic>dcpA<\/jats:italic>\n                    \u2206EAL, or\n                    <jats:italic>dcpA<\/jats:italic>\n                    D192A\/E193A, the latter two of which are defective in either PDE or DGC activity, respectively. Using these engineered strains, we examined different forms of biofilm growth, cell morphology, plastic surface adhesion, granulation, and settleability. Results of sludge volume index and microscopy indicated that the aggregates of\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    were granules rather than flocs, and the settleability of the granules was particularly robust when the cells were grown in a carbon rich medium known to promote granulation. Engineered strains sustained stable granulation more effectively than the wildtype under a low concentration Tween\u201080 treatment, which was used to induce dispersion. These results suggest that overproduction of DcpA and thus the modulated level of intracellular c\u2010di\u2010GMP enhances granulation and promotes granule persistence in\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    . Our study further demonstrates that\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    is a useful model for elucidating biological mechanisms underlying granulation, which could be leveraged to improve granular technologies for wastewater treatment.\n                  <\/jats:p>","DOI":"10.1002\/bit.70343","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T05:15:17Z","timestamp":1786598117000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Overexpression of a Gene That Modulates Cyclic\u2010di\u2010GMP Enhances Granulation in\n                    <i>Mycobacterium smegmatis<\/i>"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5604-2871","authenticated-orcid":false,"given":"Tiffany","family":"Lam","sequence":"first","affiliation":[{"name":"Department of Microbiology University of Massachusetts Amherst Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha J.","family":"Belculfine","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Massachusetts Amherst Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate N.","family":"Gregory","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Massachusetts Amherst Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph G.","family":"Gikonyo","sequence":"additional","affiliation":[{"name":"Department of Civil and Environmental Engineering University of Massachusetts Amherst Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey J.","family":"Kane","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Massachusetts Amherst Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0695-8562","authenticated-orcid":false,"given":"Chul","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Civil and Environmental Engineering University of Massachusetts Amherst Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4514-9242","authenticated-orcid":false,"given":"Yasu S.","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Massachusetts Amherst Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"14065","DOI":"10.1074\/jbc.RA118.003917","article-title":"Substrate\u2010Induced Domain Movement in a Bifunctional Protein, DcpA, Regulates Cyclic di\u2010GMP Turnover: Functional Implications of a Highly Conserved Motif","volume":"293","author":"Bharati B. 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High Granule Abundance Found in Continuous\u2010Flow Activated Sludge Treatment Plants","volume":"179","author":"Wei S. P.","year":"2020","journal-title":"Water Research"},{"key":"e_1_2_9_53_1","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.biortech.2014.08.092","article-title":"Accelerated Aerobic Granulation Using Alternating Feed Loadings: Alginate\u2010Like Exopolysaccharides","volume":"171","author":"Yang Y.\u2010C.","year":"2014","journal-title":"Bioresource Technology"}],"container-title":["Biotechnology and Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.70343","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bit.70343","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.70343","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T05:15:23Z","timestamp":1786598123000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/bit.70343"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":52,"alternative-id":["10.1002\/bit.70343"],"URL":"https:\/\/doi.org\/10.1002\/bit.70343","archive":["Portico"],"relation":{},"ISSN":["0006-3592","1097-0290"],"issn-type":[{"value":"0006-3592","type":"print"},{"value":"1097-0290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"assertion":[{"value":"2026-01-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"bit.70343"}}