{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:50:45Z","timestamp":1792788645178,"version":"4.5.0"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI154464"],"award-info":[{"award-number":["AI154464"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"New Jersey Commission on Cancer Research","award":["DFHS18PPC045"],"award-info":[{"award-number":["DFHS18PPC045"]}],"id":[{"id":"https:\/\/ror.org\/01etkt338","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (Mtb) must adapt to host-imposed stresses that limit its growth and ability to establish an infection. One important immune-regulated host defense mechanism involves competition between host and pathogen for tryptophan (Trp). Although Mtb is a Trp prototroph capable of synthesizing its own Trp, it normally acquires this amino acid from host macrophages because of the high energetic cost of its synthesis. However, interferon-\u03b3-activated macrophages attempt to restrict Mtb growth by inducing indoleamine 2,3-dioxygenase 1 (IDO1) that degrades Trp. In response, Mtb senses and adapts to limitation of this essential amino acid by inducing its own Trp biosynthetic pathway, although the mechanisms coupling Trp limitation and compensatory Trp biosynthesis remain unknown. Here, we studied the Mtb VapC37 toxin and demonstrate that it arrests growth and is a highly selective tRNase that exclusively depletes tRNA\n                    <jats:sup>Trp<\/jats:sup>\n                    . Consequently, VapC37 triggers a state of perceived Trp starvation to upregulate production of Trp biosynthetic enzymes. Therefore, this toxin appears to link intracellular Trp availability\u2014a well-established regulator of Mtb growth\u2014to a codon-dependent adaptive response to increase the Trp concentration. VapC37 also broadly reprograms the Mtb transcriptome and translatome toward synthesis of mRNAs and proteins with low or no Trp codons. However, there is one striking exception: key enzymes in the phthiocerol dimycocerosate (PDIM) biosynthetic pathway were robustly synthesized despite being large and Trp-numerous, resulting in a\u2009&gt;\u20092-fold increase in PDIM lipid production upon VapC37 expression. Thus, Mtb selectively preserves PDIM production under conditions of tRNA\n                    <jats:sup>Trp<\/jats:sup>\n                    limitation. Finally, VapBC37 and PDIM transcripts are upregulated in Mtb cells subjected to nitrosative stress and upon Mtb infection of THP-1 macrophage-like cells. This might implicate early macrophage-associated stresses as activators of VapC37, possibly enabling this toxin to reallocate metabolic priorities toward Trp biosynthesis while selectively preserving PDIM production critical for Mtb early immune escape and virulence.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014679","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:25:17Z","timestamp":1791825917000},"page":"e1014679","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Toxin-mediated tRNATrp depletion drives Trp-codon-dependent reprogramming in Mycobacterium tuberculosis while selectively enriching the PDIM biosynthetic machinery"],"prefix":"10.1371","volume":"22","author":[{"given":"Safreen","family":"Sain","sequence":"first","affiliation":[{"name":"Rutgers Health, Robert Wood Johnson Medical School","place":["Piscataway, New Jersey, United 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Medical School","place":["Piscataway, New Jersey, United States of America"],"department":["Department of Biochemistry and Molecular Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno L.","family":"Abbadi","sequence":"additional","affiliation":[{"name":"Rutgers Health, Robert Wood Johnson Medical School","place":["Piscataway, New Jersey, United States of America"],"department":["Department of Biochemistry and Molecular Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basanti","family":"Malakar","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston, Massachusetts, United States of America"],"department":["Division of Infecti ous Diseases, Department of Pediatrics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert N.","family":"Husson","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston, Massachusetts, United States of America"],"department":["Division of Infecti ous Diseases, Department of Pediatrics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3996-2990","authenticated-orcid":true,"given":"Nancy A.","family":"Woychik","sequence":"additional","affiliation":[{"name":"Rutgers Health, Robert Wood Johnson Medical School","place":["Piscataway, New Jersey, United States of America"],"department":["Department of Biochemistry and Molecular Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"ppat.1014679.ref001","unstructured":"Global tuberculosis report 2025. 2025."},{"issue":"3","key":"ppat.1014679.ref002","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.3390\/toxins6031002","article-title":"Multiple toxin-antitoxin systems in Mycobacterium tuberculosis","volume":"6","author":"A Sala","year":"2014","journal-title":"Toxins (Basel)"},{"issue":"32","key":"ppat.1014679.ref003","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2022136118","article-title":"Mycobacterium tuberculosis VapC4 toxin engages small ORFs to initiate an integrated oxidative and copper stress response","volume":"118","author":"VC Barth","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1014679.ref004","doi-asserted-by":"crossref","first-page":"5949","DOI":"10.1038\/s41598-019-41548-9","article-title":"Accurate target identification for Mycobacterium tuberculosis endoribonuclease toxins requires expression in their native host","volume":"9","author":"M Cintr\u00f3n","year":"2019","journal-title":"Sci Rep"},{"issue":"7","key":"ppat.1014679.ref005","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.adw7134","article-title":"VapC36-mediated intrinsic stress adaption is required for copper tolerance and pathogenesis of Mycobacterium 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Negatu","year":"2019","journal-title":"mBio"},{"key":"ppat.1014679.ref039","doi-asserted-by":"crossref","first-page":"3538","DOI":"10.1038\/ncomms4538","article-title":"An RNA-seq method for defining endoribonuclease cleavage specificity identifies dual rRNA substrates for toxin MazF-mt3","volume":"5","author":"JM Schifano","year":"2014","journal-title":"Nat Commun"},{"key":"ppat.1014679.ref040","volume-title":"FelixKrueger\/Trim Galore","author":"FJ Krueger","year":"2023"},{"key":"ppat.1014679.ref041","author":"S Andrews","year":"2010"},{"issue":"3","key":"ppat.1014679.ref042","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2009-10-3-r25","article-title":"Ultrafast and memory-efficient alignment of short DNA sequences to the human genome","volume":"10","author":"B Langmead","year":"2009","journal-title":"Genome Biol"},{"issue":"16","key":"ppat.1014679.ref043","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence 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