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Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1

Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1
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.
0021-9258
44025-44032
Alter-Koltunoff, M.
cab42450-fc91-4cda-940a-2864b95705a8
Ehrlich, S.
16508c3e-9800-4a90-ae0a-44631386ae05
Natalie, D.
79f2a852-0a1f-4915-b355-5166393d743e
Aviva, A.
e646c4c9-620a-4939-8176-8a4c0a5dc764
Eilers, M.
6d40aeee-22b8-4a8e-be33-d381d9743f3d
Hauser, H.
0eb2bd4b-ba0e-490e-9f16-9712f69e7da9
Bowen, H.
4ed2a24f-bf81-4d60-b475-567f9ad321bb
Barton, C.H.
5dfb4e1a-d559-4b58-9036-31de1e6c9ad8
Tamura, T.
a3507e99-df52-4fe4-b16c-f1879d53564e
Ozato, K.
6fe6ec99-c863-47d0-8ee3-b89b646a2e46
Levi, B.
0ef210f5-98aa-4d39-b104-4f3e4f8bd746
Alter-Koltunoff, M.
cab42450-fc91-4cda-940a-2864b95705a8
Ehrlich, S.
16508c3e-9800-4a90-ae0a-44631386ae05
Natalie, D.
79f2a852-0a1f-4915-b355-5166393d743e
Aviva, A.
e646c4c9-620a-4939-8176-8a4c0a5dc764
Eilers, M.
6d40aeee-22b8-4a8e-be33-d381d9743f3d
Hauser, H.
0eb2bd4b-ba0e-490e-9f16-9712f69e7da9
Bowen, H.
4ed2a24f-bf81-4d60-b475-567f9ad321bb
Barton, C.H.
5dfb4e1a-d559-4b58-9036-31de1e6c9ad8
Tamura, T.
a3507e99-df52-4fe4-b16c-f1879d53564e
Ozato, K.
6fe6ec99-c863-47d0-8ee3-b89b646a2e46
Levi, B.
0ef210f5-98aa-4d39-b104-4f3e4f8bd746

Alter-Koltunoff, M., Ehrlich, S., Natalie, D., Aviva, A., Eilers, M., Hauser, H., Bowen, H., Barton, C.H., Tamura, T., Ozato, K. and Levi, B. (2003) Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1. The Journal of Biological Chemistry, 278 (45), 44025-44032. (doi:10.1074/jbc.M307954200).

Record type: Article

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.

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Submitted date: 22 July 2003
Published date: 7 November 2003

Identifiers

Local EPrints ID: 24072
URI: https://eprints.soton.ac.uk/id/eprint/24072
ISSN: 0021-9258
PURE UUID: 88f1a56a-6e99-48d5-8c66-6669e915281b

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Date deposited: 21 Mar 2006
Last modified: 17 Jul 2017 16:15

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Contributors

Author: M. Alter-Koltunoff
Author: S. Ehrlich
Author: D. Natalie
Author: A. Aviva
Author: M. Eilers
Author: H. Hauser
Author: H. Bowen
Author: C.H. Barton
Author: T. Tamura
Author: K. Ozato
Author: B. Levi

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