A secreted Leishmania metalloprotease manipulates host iron regulation by targeting the DICER1–miRNA pathway

Micronutrient sequestration is a powerful host defense mechanism against intracellular pathogens. A key player in this is Nramp1, which effluxes iron from phagolysosomes thereby depriving the engulfed pathogens of this essential element. Leishmania major counters this by triggering hepcidin-mediated proteasomal degradation of Nramp1. Interestingly, L. major conditioned media induced hepcidin expression and Nramp1 degradation even in uninfected macrophages, resulting in enhanced endo/lysosomal iron levels. This finding suggested that a parasite-derived secretory factor was driving the effect, ultimately leading to the identification of the Leishmania metalloprotease GP63 as the mediator of Nramp1 degradation. Conditioned medium from the GP63 knockout strain (LmGP63^-/-) failed to upregulate hepcidin or degrade Nramp1. Further experiments using conditioned medium from both the wild type and LmGP63^-/- strain revealed that GP63 depletes macrophage DICER1, impairing maturation of miR-122, a negative regulator of hepcidin. Consistent with these in vitro results, the LmGP63^-/- strain, unlike its wild type counterpart, was unable to deplete DICER1, induce hepcidin expression or suppress Nramp1 in infected BALB/c mice. Collectively, we uncover a novel role for L. major-secreted GP63 in targeting the host DICER1/miR-122 axis to trigger hepcidin expression and Nramp1 degradation, facilitating iron acquisition by the parasite.