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Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1
Michal Alter-Koltunoff1, Sharon Ehrlich, Natalie Dror
1Department of Food Engineering and Biotechnology, Technion, Haifa 32000, Israel.
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.
Insights
The transcription factor IRF-8 controls Natural resistance-associated macrophage protein 1 (Nramp1) expression in immune cells. IRF-8 is crucial for innate resistance to pathogens and may play a role in autoimmune diseases.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Natural resistance-associated macrophage protein 1 (Nramp1) is vital for innate immunity against intracellular pathogens.
- Nramp1's restricted expression in macrophages suggests a specific regulatory mechanism.
- Dysregulation of Nramp1 is implicated in infectious and autoimmune diseases.
Purpose of the Study:
- To elucidate the molecular mechanisms regulating Nramp1 expression.
- To identify transcription factors involved in macrophage-specific Nramp1 control.
- To understand the role of IRF-8 in innate resistance and autoimmune disease pathogenesis.
Main Methods:
- Yeast two-hybrid screening to identify protein interactions.
- Analysis of transcription factor binding to the Nramp1 promoter.
- Phenotypic analysis of IRF-8 knockout mice challenged with pathogens.
Main Results:
- IRF-8 is identified as the key transcription factor for macrophage-specific Nramp1 expression.
- IRF-8 interacts with Miz-1 and PU.1 to bind the Nramp1 promoter.
- IRF-8 knockout mice exhibit impaired Nramp1 expression and increased susceptibility to pathogens.
Conclusions:
- IRF-8 plays a critical role in regulating Nramp1 expression, essential for innate immunity.
- The IRF-8/Miz-1/PU.1 complex mediates Nramp1 transcription in immune cells.
- IRF-8's function in Nramp1 regulation highlights its significance in host defense and potential involvement in autoimmune conditions.