Mycobacterium tuberculosis hijacks host TRIM21-and NCOA4-dependent ferritinophagy to enhance intracellular growth

Ferritin, a key regulator of iron homeostasis in macrophages, has been reported to confer host defenses against Mycobacterium tuberculosis (Mtb) infection. Nuclear receptor coactivator 4 (NCOA4) was recently identified as a cargo receptor in ferritin degradation. Here, we show that Mtb infection enhanced NCOA4-mediated ferritin degradation in macrophages, which in turn increased the bioavailability of iron to intracellular Mtb and therefore promoted bacterial growth. Of clinical relevance, the upregulation of FTH1 in macrophages was associated with tuberculosis (TB) disease progression in humans. Mechanistically, Mtb infection enhanced NCOA4-mediated ferritin degradation through p38/AKT1-and TRIM21-mediated proteasomal degradation of HERC2, an E3 ligase of NCOA4. Finally, we confirmed that NCOA4 deficiency in myeloid cells expedites the clearance of Mtb infection in a murine model. Together, our findings revealed a strategy by which Mtb hijacks host ferritin metabolism for its own intracellular survival. Therefore, this represents a potential target for host -directed therapy against tuberculosis.

Automated summary

Ferritin regulates iron homeostasis in macrophages and defends against Mycobacterium tuberculosis (Mtb) infection. NCOA4 is a cargo receptor involved in ferritin degradation, and Mtb infection enhances NCOA4-mediated ferritin degradation in macrophages, promoting bacterial growth. Clinical data also shows that the upregulation of FTH1 in macrophages is associated with tuberculosis (TB) disease progression. Mechanistically, Mtb infection enhances NCOA4-mediated ferritin degradation through the degradation of HERC2, an E3 ligase of NCOA4. Furthermore, NCOA4 deficiency in myeloid cells accelerates the clearance of Mtb infection in a murine model. These findings suggest that targeting host ferritin metabolism could be a potential strategy for host-directed therapy against tuberculosis.