Mycobacterium tuberculosis induces host autophagic ferritin degradation for enhanced iron bioavailability and bacterial growth

Abstract

ABSTRACT To prevent Mycobacterium tuberculosis (Mtb) infection, the host can restrict iron availability via iron-chelation proteins such as ferritin, which is a key regulator of iron homeostasis in macrophages. However, how Mtb escapes the nutrient immunity mediated by ferritin and survives in the infected host despite ongoing immune responses remains unclear. Our recent findings demonstrated that Mtb exploited the autophagic degradation of ferritin mediated by a selective autophagy receptor, nuclear receptor coactivator 4 (NCOA4), in macrophages for enhanced iron bioavailability and bacterial growth. Further, we found that ferritin degradation in macrophages is involved in human tuberculosis disease progression. Mechanistically, Mtb-induced ferritin degradation is initiated by p38 protein kinase (p38) and AKT serine/threonine kinase 1 (AKT1) signaling and mediated by a tripartite motif containing 21 (TRIM21)-dependent proteasomal degradation cascade. Finally, we used a mouse model with NCOA4-deficient myeloid cells to confirm their role in resistance to Mtb infection. Our study thus identifies modulation of host ferritin metabolism as a novel Mtb strategy for intracellular growth, which may provide a potential target for host-directed therapy against tuberculosis. Abbreviations Mtb, Mycobacterium tuberculosis; TB, tuberculosis; NCOA4, nuclear receptor coactivator 4; p38, p38 protein kinase; AKT1, AKT serine/threonine kinase 1; TRIM21, tripartite motif containing 21; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; HERC2, HECT and RLD domain containing E3 ubiquitin protein ligase 2.