Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1.
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.
Alter-Koltunoff
Michal
M
Department of Food Engineering and Biotechnology, Technion, Haifa 32000, Israel.
Ehrlich
Sharon
S
Dror
Natalie
N
Azriel
Aviva
A
Eilers
Martin
M
Hauser
Hansjörg
H
Bowen
Holly
H
Barton
C Howard
CH
Tamura
Tomohiko
T
Ozato
Keiko
K
Levi
Ben-Zion
BZ
D000818:Animals; D001327:Autoimmune Diseases; D019556:COS Cells; D027682:Cation Transport Proteins / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D018922:HL-60 Cells; D006801:Humans; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D014157:Transcription Factors; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; D000099173:Natural Resistance-associated Macrophage Protein 1; C107961:ZBTB17 protein, human