{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:12:31Z","timestamp":1790766751690,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010475","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000}}],"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T00:00:00Z","timestamp":1649980800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009053","name":"The Wellcome Trust DBT India Alliance","doi-asserted-by":"publisher","award":["IA\/S\/16\/2\/502700"],"award-info":[{"award-number":["IA\/S\/16\/2\/502700"]}],"id":[{"id":"10.13039\/501100009053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["BT\/PR13522\/COE\/34\/27\/2015,BT\/PR29098\/Med\/29\/1324\/2018, BT\/HRD\/NBA\/39\/07\/2018-19, and BT\/PR39308\/DRUG\/134\/86\/2021"],"award-info":[{"award-number":["BT\/PR13522\/COE\/34\/27\/2015,BT\/PR29098\/Med\/29\/1324\/2018, BT\/HRD\/NBA\/39\/07\/2018-19, and BT\/PR39308\/DRUG\/134\/86\/2021"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DBT-IISc Partnership Program","award":["22-0905-0006-05-987-436"],"award-info":[{"award-number":["22-0905-0006-05-987-436"]}]},{"name":"DST-FIST"},{"name":"Revati and Satya Nadham Atluri Chair Professorship"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Iron-sulfur (Fe-S) cluster proteins carry out essential cellular functions in diverse organisms, including the human pathogen <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>). The mechanisms underlying Fe-S cluster biogenesis are poorly defined in <jats:italic>Mtb<\/jats:italic>. Here, we show that <jats:italic>Mtb<\/jats:italic> SufT (Rv1466), a DUF59 domain-containing essential protein, is required for the Fe-S cluster maturation. <jats:italic>Mtb<\/jats:italic> SufT homodimerizes and interacts with Fe-S cluster biogenesis proteins; SufS and SufU. SufT also interacts with the 4Fe-4S cluster containing proteins; aconitase and SufR. Importantly, a hyperactive cysteine in the DUF59 domain mediates interaction of SufT with SufS, SufU, aconitase, and SufR. We efficiently repressed the expression of SufT to generate a SufT knock-down strain in <jats:italic>Mtb<\/jats:italic> (SufT-KD) using CRISPR interference. Depleting SufT reduces aconitase\u2019s enzymatic activity under standard growth conditions and in response to oxidative stress and iron limitation. The SufT-KD strain exhibited defective growth and an altered pool of tricarboxylic acid cycle intermediates, amino acids, and sulfur metabolites. Using Seahorse Extracellular Flux analyzer, we demonstrated that SufT depletion diminishes glycolytic rate and oxidative phosphorylation in <jats:italic>Mtb<\/jats:italic>. The SufT-KD strain showed defective survival upon exposure to oxidative stress and nitric oxide. Lastly, SufT depletion reduced the survival of <jats:italic>Mtb<\/jats:italic> in macrophages and attenuated the ability of <jats:italic>Mtb<\/jats:italic> to persist in mice. Altogether, SufT assists in Fe-S cluster maturation and couples this process to bioenergetics of <jats:italic>Mtb<\/jats:italic> for survival under low and high demand for Fe-S clusters.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010475","type":"journal-article","created":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T17:35:53Z","timestamp":1650044153000},"page":"e1010475","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":30,"title":["Mycobacterium tuberculosis requires SufT for Fe-S cluster maturation, metabolism, and survival in vivo"],"prefix":"10.1371","volume":"18","author":[{"given":"Ashutosh","family":"Tripathi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kushi","family":"Anand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayashree","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchika Annie","family":"O\u2019Niel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabarinath","family":"P. S","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrani","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghunatha Reddy","family":"R. L.","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raju S.","family":"Rajmani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagasuma","family":"Chandra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Laxman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6761-1664","authenticated-orcid":true,"given":"Amit","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,4,15]]},"reference":[{"issue":"4","key":"ppat.1010475.ref001","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1111\/j.1365-2958.2006.05028.x","article-title":"Iron-sulphur clusters and the problem with oxygen","volume":"59","author":"JA Imlay","year":"2006","journal-title":"Mol Microbiol"},{"issue":"2","key":"ppat.1010475.ref002","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1074\/jbc.M607646200","article-title":"Micromolar intracellular hydrogen peroxide disrupts metabolism by damaging iron-sulfur enzymes","volume":"282","author":"S Jang","year":"2007","journal-title":"J Biol Chem"},{"issue":"43","key":"ppat.1010475.ref003","doi-asserted-by":"crossref","first-page":"44590","DOI":"10.1074\/jbc.M406487200","article-title":"Repair of oxidized iron-sulfur clusters in Escherichia coli","volume":"279","author":"O Djaman","year":"2004","journal-title":"J Biol Chem"},{"issue":"28","key":"ppat.1010475.ref004","doi-asserted-by":"crossref","first-page":"11562","DOI":"10.1073\/pnas.0700490104","article-title":"Mycobacterium tuberculosis WhiB3 responds to O2 and nitric oxide via its [4Fe-4S] cluster and is essential for nutrient starvation survival","volume":"104","author":"A Singh","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"ppat.1010475.ref005","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1000545","article-title":"Mycobacterium tuberculosis WhiB3 Maintains redox homeostasis by regulating virulence lipid anabolism to modulate macrophage response.","volume":"5","author":"A Singh","year":"2009","journal-title":"PLoS Pathog."},{"issue":"6","key":"ppat.1010475.ref006","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1111\/j.1365-2958.2012.08165.x","article-title":"Mycobacterium tuberculosis WhiB4 regulates oxidative stress response to modulate survival and dissemination in vivo","volume":"85","author":"M Chawla","year":"2012","journal-title":"Mol Microbiol"},{"key":"ppat.1010475.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.25624","article-title":"Efficacy of \u03b2-lactam\/\u03b2-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis.","volume":"6","author":"S Mishra","year":"2017","journal-title":"Elife"},{"issue":"6","key":"ppat.1010475.ref008","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1074\/jbc.M115.684597","article-title":"Mycobacterium tuberculosis WhiB3 Responds to vacuolar pH-induced changes in mycothiol redox potential to modulate phagosomal maturation and virulence","volume":"291","author":"M Mehta","year":"2016","journal-title":"J Biol Chem"},{"key":"ppat.1010475.ref009","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.freeradbiomed.2018.11.032","article-title":"Mycobacterium tuberculosis WhiB3 maintains redox homeostasis and survival in response to reactive oxygen and nitrogen species","volume":"131","author":"M Mehta","year":"2019","journal-title":"Free Radic Biol Med"},{"issue":"17","key":"ppat.1010475.ref010","doi-asserted-by":"crossref","first-page":"8452","DOI":"10.1093\/nar\/gkv854","article-title":"A unique uracil-DNA binding protein of the uracil DNA glycosylase superfamily","volume":"43","author":"PB Sang","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"17","key":"ppat.1010475.ref011","doi-asserted-by":"crossref","first-page":"6137","DOI":"10.1128\/JB.187.17.6137-6146.2005","article-title":"Identification of the Mycobacterium tuberculosis SUF machinery as the exclusive mycobacterial system of [Fe-S] cluster assembly: Evidence for its implication in the pathogen\u2019s survival","volume":"187","author":"G Huet","year":"2005","journal-title":"J Bacteriol"},{"issue":"18","key":"ppat.1010475.ref012","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1128\/JB.00359-16","article-title":"Iron homeostasis in Mycobacterium tuberculosis: Mechanistic insights into siderophore-mediated Iron uptake","volume":"198","author":"M. 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