Leishmania secretory factor GP63 targets the DICER1/miR-122/hepcidin axis in host macrophages to deplete Nramp1

ABSTRACT Micronutrient sequestration is a powerful host defense against intracellular pathogens. A key player in this is Nramp1, which effluxes iron from phagolysosomes, depriving the engulfed pathogens of this essential element. Leishmania counters this by triggering hepcidin-mediated proteasomal degradation of Nramp1. Interestingly, Leishmania major conditioned media induced hepcidin expression and Nramp1 degradation even in uninfected macrophages, resulting in enhanced endo/lysosomal iron. This observation led to the identification of the secretory factor GP63 responsible for Nramp1 degradation. Conditioned media from the LmGP63−/- strain failed to upregulate hepcidin or degrade Nramp1. Further, GP63 was found to deplete macrophage DICER1, impairing maturation of miR-122, a negative regulator of hepcidin. Consistent with in vitro results, the LmGP63−/- strain, unlike its wild type counterpart, was unable to deplete DICER1, induce hepcidin expression or suppress Nramp1 in infected mice. Collectively, we uncover a novel role for Leishmania GP63 in targeting the host DICER1/miR-122 axis to trigger hepcidin expression and Nramp1 degradation, facilitating iron acquisition by the parasite. SUMMARY This study uncovers a novel role for the Leishmania secretory protein GP63 in targeting the DICER1/miR-122 axis in host macrophages to upregulate hepcidin and promote Nramp1 degradation. By employing this strategy, Leishmania parasites boost iron availability in their replication niche. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵# Department of Biochemistry, University of Cambridge, United Kingdom. Some minor modifications were made in the manuscript texts