Abstract
Natural resistance-associated macrophage protein 1 (Nramp1) is a proton/divalent cation antiporter exclusively expressed in monocyte/macrophage cells with a unique role in innate resistance to intraphagosomal pathogens. In humans, it is linked to several infectious diseases, including leprosy, pulmonary tuberculosis, visceral leishmaniasis, meningococcal meningitis, and human immunodeficiency virus as well as to autoimmune diseases such as rheumatoid arthritis and Crohn's disease. Here we demonstrate that the restricted expression of Nramp1 is mediated by the macrophage-specific transcription factor IRF-8. This factor exerts its activity via protein-protein interaction, which facilitates its binding to target DNA. Using yeast two-hybrid screen we identified Myc Interacting Zinc finger protein 1 (Miz-1) as new interacting partner. This interaction is restricted to immune cells and takes place on the promoter Nramp1 in association with PU.1, a transcription factor essential for myelopoiesis. Consistent with these data, IRF-8 knockout mice are sensitive to a repertoire of intracellular pathogens. Accordingly, IRF-8-/- mice express low levels of Nramp1 that can not be induced any further. Thus, our results explain in molecular terms the role of IRF-8 in conferring innate resistance to intracellular pathogens and point to its possible involvement in autoimmune diseases.
Highlights
Macrophages are essential components of innate immunity and provide important links between innate and adaptive immunity
It was shown that the transcription factor Myc interacting zinc-finger protein 1 (Miz-1) mediates the activation of natural resistanceassociated macrophage protein 1 (Nramp1) that can be repressed by c-Myc (25)
This is supported by the fact that the macrophage cell line derived from IRF-8 null mice failed to express significant levels of mRNA corresponding to Nramp1, and the low basal level could not be further induced by IFN-␥ and LPS as in wild type cells (40)
Summary
Vol 278, No 45, Issue of November 7, pp. 44025–44032, 2003 Printed in U.S.A. Nramp1-mediated Innate Resistance to Intraphagosomal Pathogens Is Regulated by IRF-8, PU., and Miz-1*. Using yeast two-hybrid screen we identified Myc Interacting Zinc finger protein 1 (Miz-1) as new interacting partner This interaction is restricted to immune cells and takes place on the promoter Nramp in association with PU., a transcription factor essential for myelopoiesis. It was shown that IRF-8 is an essential factor for proper functioning of mature macrophages It is essential for the regulated expression of specific phagosomal components like phagocyte oxidase complex (gp91phox and p67phox (15), iNOS (16), and Nramp (as shown here)). The data collected from such screen suggested that IRF-8 is engaged in numerous associations with additional transcription factors In this communication, we report the cloning of Myc interacting zinc-finger protein 1 (Miz-1) as a new interacting partner with IRF-8 identified in yeast cells. Our results lay the molecular basis for the regulated expression of Nramp in macrophages and explain in molecular terms the role of IRF-8 in conferring innate resistance to intracellular pathogens
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
