{ "abstract": "Mycobacterium tuberculosis (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-γ-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 tRNATrp. 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—a well-established regulator of Mtb growth—to 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 > 2-fold increase in PDIM lipid production upon VapC37 expression. Thus, Mtb selectively preserves PDIM production under conditions of tRNATrp 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. Author summary: Tryptophan (Trp), the least abundant amino acid in Escherichia coli, is likely also limiting in Mycobacterium tuberculosis (Mtb) since intracellular Trp concentration acts as a growth regulating switch. Although Mtb is a prototroph capable of synthesizing its own Trp, this pathway is energetically costly. Macrophage-residing Mtb cells are therefore thought to exploit the host environment as an exogenous source of Trp. In response, the host innate immune system restricts bacterial growth through interferon-γ-induced degradation of Trp. Although Trp availability is essential to establish an infection in mice, it is unclear how Mtb senses and adapts to host-imposed Trp limitation. Here we report that the VapC37 toxin might help Mtb adapt to the Trp-restricted environment encountered during macrophage infection. VapC37-mediated tRNATrp inactivation mimics Trp starvation and triggers the Trp biosynthetic pathway that may counter host-imposed Trp stress while simultaneously remodeling Mtb physiology and upregulating the phthiocerol dimycocerosate (PDIM) lipid biosynthetic pathway essential for Mtb virulence. VapC37 and PDIM biosynthetic transcripts are upregulated during infection of THP-1 macrophage-like cells, and VapC37 transcripts are also induced by nitrosative stress. Together, these findings implicate VapC37 as a possible mediator that links growth arrest, Trp biosynthesis, metabolic adaptation, and preservation of virulence during infection.", "abstract_shown": true, "affiliations": [ "Department of Biochemistry and Molecular Biology, Rutgers Health, Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America", "Division of Infecti ous Diseases, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 8, "authors": [ { "affs": [ 0 ], "name": "Safreen Sain" }, { "affs": [ 1 ], "name": "Unnati Chauhan" }, { "name": "Valdir C. Barth Jr" }, { "name": "Eduardo A. Troian" }, { "name": "Bruno L. Abbadi" }, { "name": "Basanti Malakar" }, { "name": "Robert N. Husson" }, { "name": "Nancy A. Woychik" } ], "bibtex": "https://research.draconitic.com/paper/0ne5ne6yszw76.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014679", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014679", "id": "0ne5ne6yszw76", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014679", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2725|Tuberculosis Research and Epidemiology" ], [ "plos", "/Biology and life sciences/Biochemistry/Biosynthesis" ], [ "plos", "/Biology and life sciences/Biochemistry/Lipids" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Non-coding RNA/Transfer RNA" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Protein structure/Protein folding" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Protein synthesis" ], [ "plos", "/Biology and life sciences/Molecular biology/Macromolecular structure analysis/Protein structure/Protein folding" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Sequencing techniques/RNA sequencing" ], [ "plos", "/Biology and life sciences/Organisms/Bacteria/Actinobacteria/Mycobacterium tuberculosis" ], [ "plos", "/Biology and life sciences/Toxicology/Toxic agents/Toxins" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Toxicology/Toxic agents/Toxins" ], [ "plos", "/Research and analysis methods/Chemical synthesis/Biosynthetic techniques/Protein synthesis" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Sequencing techniques/RNA sequencing" ] ], "openalex": "W7221503631", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014679&type=printable", "pmcid": "PMC13657306", "pmid": null, "published": "2026-10-01", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/0ne5ne6yszw76.ris", "sources": [ { "first_seen": "2026-10-30T12:17:30Z", "native_id": "10.1371/journal.ppat.1014679", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014679" }, { "first_seen": "2026-10-30T12:17:31Z", "native_id": "PMC:PMC13657306", "source": "europepmc", "url": "https://europepmc.org/article/PMC/PMC13657306" } ], "subjects": [ { "field": "biochemistry", "origin": "plos:molecular biology", "subfield": "molecular-biology" }, { "field": "medicine", "origin": "plos:toxicology", "subfield": "pharmacology-toxicology" } ], "title": "Toxin-mediated tRNATrp depletion drives Trp-codon-dependent reprogramming in Mycobacterium tuberculosis while selectively enriching the PDIM biosynthetic machinery", "title_text": "Toxin-mediated tRNATrp depletion drives Trp-codon-dependent reprogramming in Mycobacterium tuberculosis while selectively enriching the PDIM biosynthetic machinery", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:31Z", "url": "https://research.draconitic.com/paper/0ne5ne6yszw76", "venue": "PLOS Pathogens", "versions": [] }