{
  "abstract": "Mycobacterium tuberculosis (Mtb) increases the availability of free iron, resulting in ferroptosis of macrophages to facilitate its survival and dissemination. A critical factor for elevated levels of labile iron is the overt accumulation of nuclear receptor coactivator 4 (NCOA4), which promotes autophagic degradation of ferritin in a process termed ferritinophagy. Here, we identify a novel post-translational modification on NCOA4 that is essential for its interaction with ferritin in the iron-replete condition of Mtb-infected cells. Specifically, protein arginine methyltransferase 5 (PRMT5) confers symmetric dimethylation on NCOA4, which promotes ferritinophagy-mediated ferroptosis. Using loss-of-function studies, we show that PRMT5 is required for lipid peroxidation, bacterial survival, and dissemination in Mtb-infected mice. Additionally, the overexpression of a methylation-deficient mutant of NCOA4 phenocopies the depletion of PRMT5 and reduces ferritinophagy in Mtb-infected cells. Mechanistically, we identify that PRMT5-mediated methylation enhances the cytoplasmic retention of NCOA4 and reduces its nuclear availability. Thus, our findings uncover the key interaction between NCOA4 and ferritin that regulates ferroptosis and mycobacterial survival during infection. Perturbation of this interaction results in reduced Mtb loads and alleviated disease pathology. Author summary: Ferroptosis, an iron-dependent form of necrotic cell death has emerged as a crucial determinant of Mycobacterium tuberculosis pathogenesis with implications in dissemination, tissue damage and pathology. A pre-requisite for the induction of ferroptosis is the availability of labile iron, which is sequestered within an intracellular storage protein, ferritin, to limit bioavailability. Upon requirement, the cargo receptor, NCOA4, binds and targets ferritin for autophagic degradation in a process termed as ferritinophagy. This study elucidates a crucial methylation on NCOA4, that disrupts the homeostatic control, promotes its interaction with ferritin and leads to aberrant accumulation of ferrous ions within infected macrophages.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India",
    "Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, Karnataka, India"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Smriti Sundar"
    },
    {
      "affs": [
        1
      ],
      "name": "Raju S. Rajmani"
    },
    {
      "name": "Kithiganahalli Narayanaswamy Balaji"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1qfxy0kaksj63.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.ppat.1014614",
  "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014614",
  "id": "1qfxy0kaksj63",
  "issns": [
    "1553-7374"
  ],
  "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014614",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "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/Proteins/Amino acids/Basic amino acids/Arginine"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Protein complexes/Ferritin"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Molecular biology/Molecular biology techniques/Molecular probe techniques/Immunoblotting"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Actinobacteria/Mycobacterium tuberculosis"
    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical compounds/Organic compounds/Amino acids/Basic amino acids/Arginine"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical reactions/Methylation"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Organic chemistry/Organic compounds/Amino acids/Basic amino acids/Arginine"
    ],
    [
      "plos",
      "/Research and analysis methods/Molecular biology techniques/Molecular probe techniques/Immunoblotting"
    ],
    [
      "plos",
      "/Research and analysis methods/Specimen preparation and treatment/Staining/Cell staining"
    ],
    [
      "plos",
      "/Research and analysis methods/Specimen preparation and treatment/Staining/Nuclear staining"
    ]
  ],
  "openalex": "W7214011629",
  "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014614&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-22",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/1qfxy0kaksj63.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "10.1371/journal.ppat.1014614",
      "source": "plos",
      "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014614"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:molecular biology",
      "subfield": "molecular-biology"
    },
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "plos:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Role of PRMT5 in regulating ferritinophagy during Mycobacterium tuberculosis infection",
  "title_text": "Role of PRMT5 in regulating ferritinophagy during Mycobacterium tuberculosis infection",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:43Z",
  "url": "https://research.draconitic.com/paper/1qfxy0kaksj63",
  "venue": "PLOS Pathogens",
  "versions": []
}