Open AccessLeishmania donovani inhibits ferroportin translation by modulating FBXL5‐IRP2 axis for its growth within host macrophages
Author(s) -
Das Nupur Kanti,
Sandhya Sandhya,
G. Vishnu Vivek,
Kumar Rajiv,
Singh Amit Kumar,
Bal Saswat Kumar,
Kumari Sanju,
Mukhopadhyay Chinmay K.
Publication year - 2018
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12834
Subject(s) - ferroportin , biology , translation (biology) , leishmania , leishmania donovani , macrophage , microbiology and biotechnology , hepcidin , in vivo , ferritin , visceral leishmaniasis , inflammation , immunology , in vitro , messenger rna , leishmaniasis , biochemistry , gene , genetics , parasite hosting , world wide web , computer science
Hepcidin mediated ferroportin (Fpn) degradation in macrophages is a well adopted strategy to limit iron availability towards invading pathogens. Leishmania donovani (LD), a protozoan parasite, resides within macrophage and competes with host for availing iron. Using in vitro and in vivo model of infection, we reveal that LD decreases Fpn abundance in host macrophages by hepcidin independent mechanism. Unaffected level of Fpn‐FLAG in LD infected J774 macrophage confirms that Fpn down‐regulation is not due its degradation. While increased Fpn mRNA but decreased protein expression in macrophages suggests blocking of Fpn translation by LD infection that is confirmed by 35 S‐methionine labelling assay. We further reveal that LD blocks Fpn translation by induced binding of iron regulatory proteins (IRPs) to the iron responsive element present in its 5′UTR. Supershift analysis provides evidence of involvement of IRP2 particularly during in vivo infection. Accordingly, a significant increase in IRP2 protein expression with simultaneous decrease in its stability regulator F‐box and leucine‐rich repeat Protein 5 (FBXL5) is detected in splenocytes of LD‐infected mice. Increased intracellular growth due to compromised expressions of Fpn and FBXL5 by specific siRNAs reveals that LD uses a novel strategy of manipulating IRP2‐FBXL5 axis to inhibit host Fpn expression.