{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:08:56Z","timestamp":1791313736858,"version":"4.3.1"},"reference-count":61,"publisher":"Microbiology Society","issue":"2","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"crossref","award":["JBR\/2021\/000020"],"award-info":[{"award-number":["JBR\/2021\/000020"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"crossref","award":["BT\/PR20242\/MED\/29\/1062\/2016"],"award-info":[{"award-number":["BT\/PR20242\/MED\/29\/1062\/2016"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Council for Scientific and Industrial Research, Government of India","award":["21(1088)\/19\/EMR-II"],"award-info":[{"award-number":["21(1088)\/19\/EMR-II"]}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"crossref","award":["45\/8\/2019-PHY\/BMS"],"award-info":[{"award-number":["45\/8\/2019-PHY\/BMS"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"crossref","award":["45\/1\/2020-IMM\/BMS"],"award-info":[{"award-number":["45\/1\/2020-IMM\/BMS"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"crossref","award":["BMI\/11(90)\/2022"],"award-info":[{"award-number":["BMI\/11(90)\/2022"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,7]]},"abstract":"<jats:p>Cyclic-di-guanosine monophosphate (c-di-GMP) plays an important role in bacterial signalling networks. C-di-GMP exerts a regulatory function through binding to diverse molecules that include transcription factors, riboswitches and sensor kinases (SKs), thereby regulating diverse processes. Here, we demonstrate the crosstalk between c-di-GMP and the SK MtrB of <jats:italic>Mycobacterium tuberculosis<\/jats:italic>. MtrB phosphorylates and regulates its cognate response regulator MtrA. C-di-GMP binds directly to the cytosolic domain of MtrB to inhibit its autophosphorylation. C-di-GMP levels in <jats:italic>M. tuberculosis<\/jats:italic> were manipulated by overexpressing a c-di-GMP synthesizing enzyme <jats:italic>ydeH<\/jats:italic> and a degrading enzyme <jats:italic>rv1357c<\/jats:italic>. We demonstrate that overexpression of <jats:italic>ydeH<\/jats:italic> lowers growth of the bacterium both <jats:italic>in vitro<\/jats:italic> and in <jats:italic>M. tuberculosis<\/jats:italic> grown in macrophages. This is in conformity with lowered expression of <jats:italic>mtrA<\/jats:italic> and selected genes of the <jats:italic>mtrA<\/jats:italic> regulon involved in cell wall turnover in the <jats:italic>ydeH<\/jats:italic>-overexpressing strain compared to the parent strain. We also demonstrate that overexpression of <jats:italic>ydeH<\/jats:italic> in <jats:italic>M. tuberculosis<\/jats:italic> hinders biofilm formation, whereas overexpression of <jats:italic>rv1357c<\/jats:italic> has the opposite effect. Neither of the two genes could rescue the biofilm defective phenotype of the MtrB knock out mutant (<jats:italic>\u0394mtrB<\/jats:italic>), suggesting that c-di-GMP exerts its role on biofilm formation through MtrB. Finally, we show by fluorescence microscopy that the trafficking of <jats:italic>M. tuberculosis<\/jats:italic> overexpressing <jats:italic>ydeH<\/jats:italic> is significantly higher than that of the parent strain and that this is linked to reduced expression of the MtrB-dependent genes <jats:italic>esxG<\/jats:italic> and <jats:italic>esxH<\/jats:italic>, which play a role in subversion of lysosomal trafficking of <jats:italic>M. tuberculosis<\/jats:italic>. These results provide important new insight into the crosstalk between c-di-GMP and MtrB in <jats:italic>M. tuberculosis<\/jats:italic>.<\/jats:p>","DOI":"10.1099\/mic.0.001532","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T18:16:43Z","timestamp":1738952203000},"source":"Crossref","is-referenced-by-count":5,"title":["Crosstalk between cyclic-di-guanosine monophosphate and the sensor kinase MtrB regulates MtrA-dependent genes, bacterial growth, biofilm formation and lysosomal trafficking of Mycobacterium tuberculosis"],"prefix":"10.1099","volume":"171","author":[{"given":"Shreya","family":"Bagchi","sequence":"first","affiliation":[{"name":"Department of Chemical Sciences, Bose Institute, 93\/1 APC Road, Kolkata 700009, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun Kumar","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, Bose Institute, 93\/1 APC Road, Kolkata 700009, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya","family":"Mal","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Bose Institute, Unified Academic Campus, EN 80, Sector V, Bidhan Nagar, Kolkata 700091, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manikuntala","family":"Kundu","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, Bose Institute, 93\/1 APC Road, Kolkata 700009, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0497-9581","authenticated-orcid":false,"given":"Joyoti","family":"Basu","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, Bose Institute, 93\/1 APC Road, Kolkata 700009, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"345","reference":[{"key":"R1","article-title":"Global Tuberculosis Report 2022"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1872"},{"key":"R3","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1111\/mmi.14899","article-title":"Two\u2010component sensor histidine kinases of Mycobacterium tuberculosis: beacons for niche navigation","volume":"117","author":"Stupar","year":"2022","journal-title":"Mol Microbiol"},{"key":"R4","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1111\/j.1365-2958.2008.06483.x","article-title":"A matter of life and death: cell wall homeostasis and the WalKR (YycGF) essential signal transduction pathway","volume":"70","author":"Dubrac","year":"2008","journal-title":"Mol Microbiol"},{"key":"R5","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1111\/j.1365-2958.2010.07464.x","article-title":"A role for the essential yycg sensor histidine kinase in sensing cell division","volume":"79","author":"Fukushima","year":"2011","journal-title":"Mol Microbiol"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00645-07"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2004.04249.x"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.009449"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05137.x"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.040097"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.346544"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.000585"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.000087"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01795-14"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40095-2"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1093\/femspd\/fty048"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-020518-115555"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00043-12"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1038\/nature14473"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14585-6"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007952"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111515"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky146"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44774-6"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1111\/1462-2920.15987"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-61815-8"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002537RR"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1111\/febs.17261"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.13991"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20150268"},{"key":"R31","first-page":"10,1519.","article-title":"Recombinant BCG with bacterial signaling molecule cyclic di-AMP as endogenous adjuvant induces elevated immune responses after Mycobacterium tuberculosis infection","author":"Ning","year":"2019","journal-title":"Front Immunol"},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/8237402"},{"key":"R33","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.chom.2007.09.006","article-title":"Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental cues","volume":"2","author":"Rohde","year":"2007","journal-title":"Cell Host Microbe"},{"key":"R34","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/nature10429","article-title":"STING is a direct innate immune sensor of cyclic di-GMP","volume":"478","author":"Burdette","year":"2011","journal-title":"Nature"},{"key":"R35","doi-asserted-by":"crossref","first-page":"e0256664","DOI":"10.1371\/journal.pone.0256664","article-title":"A high-frequency single nucleotide polymorphism in the MtrB sensor kinase in clinical strains of Mycobacterium tuberculosis alters its biochemical and physiological properties","volume":"16","author":"Waturuocha","year":"2021","journal-title":"PLoS One"},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.15119"},{"key":"R37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015072"},{"key":"R38","doi-asserted-by":"publisher","DOI":"10.1007\/s12010-010-9017-x"},{"key":"R39","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.02839"},{"key":"R40","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.516315"},{"key":"R41","doi-asserted-by":"publisher","DOI":"10.1128\/JB.182.13.3832-3838.2000"},{"key":"R42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R115.711507"},{"key":"R43","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1353"},{"key":"R44","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2018.03.014"},{"key":"R45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003734"},{"key":"R46","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-022-01130-y"},{"key":"R47","first-page":"3","volume-title":"Cyclic Dinucleotide Signaling in Mycobacteria Microbial Cyclic Di-Nucleotide Signaling in Microbial Cyclic Di-Nucleotide Signalling","author":"Petchiappan","year":"2020"},{"key":"R48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.008252"},{"key":"R49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1911427117"},{"key":"R50","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.05004-11"},{"key":"R51","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00111-18"},{"key":"R52","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.06.002"},{"key":"R53","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00222-13"},{"key":"R54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21748-6"},{"key":"R55","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.09.016"},{"key":"R56","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-91993-8"},{"key":"R57","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2023.04.065"},{"key":"R58","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06289-7"},{"key":"R59","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.11.023"},{"key":"R60","doi-asserted-by":"publisher","DOI":"10.3390\/biology9120443"},{"key":"R61","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.08.014"}],"container-title":["Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/micro\/10.1099\/mic.0.001532?crawler=true&mimetype=application\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T18:16:51Z","timestamp":1738952211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/micro\/10.1099\/mic.0.001532"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,7]]},"references-count":61,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2,7]]}},"URL":"https:\/\/doi.org\/10.1099\/mic.0.001532","relation":{},"ISSN":["1350-0872","1465-2080"],"issn-type":[{"value":"1350-0872","type":"print"},{"value":"1465-2080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,7]]}}}