Tuberculosis exploits PRMT5 to trigger ferroptosis via NCOA4

Tuberculosis remains a major infectious threat in which the bacterium Mycobacterium tuberculosis (Mtb) manipulates the host cell to survive and spread. One way Mtb does this is by increasing the availability of free iron inside infected macrophages, causing a form of cell death called ferroptosis. Researchers led by Kithiganahalli Narayanaswamy Balaji set out to understand how levels of labile iron rise during infection. They focused on nuclear receptor coactivator 4 (NCOA4), a protein that drives autophagic degradation of ferritin in a process called ferritinophagy; this breakdown of ferritin releases the iron that can fuel ferroptosis. The team discovered a previously unknown chemical modification on NCOA4 that is tied to its ability to bind ferritin when cells are iron-replete during Mtb infection. Rather than changes in gene expression alone, this work points to a post-translational change on the NCOA4 protein itself as a key step in how Mtb reshapes iron handling inside host cells to its advantage.

The investigators identified protein arginine methyltransferase 5 (PRMT5) as the enzyme that places a symmetric-dimethylation mark on NCOA4. This PRMT5-mediated methylation promoted the interaction between NCOA4 and ferritin, driving ferritinophagy and subsequent ferroptosis in infected cells. Using loss-of-function studies, the team showed that PRMT5 was required for lipid peroxidation, bacterial survival, and dissemination in Mtb-infected mice, linking the enzyme directly to processes that help the pathogen persist. Complementary experiments showed that overexpression of a methylation-deficient mutant of NCOA4 phenocopied depletion of PRMT5: cells expressing the mutant had reduced ferritinophagy during Mtb infection. The researchers also found that PRMT5-mediated methylation reduced the nuclear availability of NCOA4 and impaired its co-activatory role with nuclear receptors such as vitamin D3, revealing both a cytoplasmic and nuclear consequence of the modification.

These findings reveal a precise molecular interaction that Mtb exploits to shift iron biology inside host cells and promote its own survival. By showing that methylation of NCOA4 by PRMT5 is necessary for ferritinophagy-driven ferroptosis, the work points to a single post-translational modification as a control point that determines whether infected macrophages undergo damaging lipid peroxidation. Importantly, perturbing this interaction—either by removing PRMT5 function or by expressing a methylation-deficient NCOA4—reduced Mtb loads and alleviated disease pathology in the models used. That suggests new conceptual routes for interventions: rather than directly targeting the bacterium, approaches that block PRMT5 activity or prevent NCOA4 methylation could limit the iron-driven cell death Mtb needs to disseminate. The study also raises questions about how changes in NCOA4 localization and its impaired co-activation of nuclear receptors like vitamin D3 contribute to the wider immune response during tuberculosis.