The hemochromatosis protein HFE inhibits iron export from macrophages.
Hereditary hemochromatosis (HH) is a disorder of iron metabolism caused by common mutations in the gene HFE. The HFE protein binds to transferrin receptor-1 (TfR1) in competition with transferrin, and in vitro, reduces cellular iron by reducing iron uptake. However, in vivo, HFE is strongly expresse...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2002
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| _version_ | 1826289742680948736 |
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| author | Drakesmith, H Sweetland, E Schimanski, L Edwards, J Cowley, D Ashraf, M Bastin, J Townsend, A |
| author_facet | Drakesmith, H Sweetland, E Schimanski, L Edwards, J Cowley, D Ashraf, M Bastin, J Townsend, A |
| author_sort | Drakesmith, H |
| collection | OXFORD |
| description | Hereditary hemochromatosis (HH) is a disorder of iron metabolism caused by common mutations in the gene HFE. The HFE protein binds to transferrin receptor-1 (TfR1) in competition with transferrin, and in vitro, reduces cellular iron by reducing iron uptake. However, in vivo, HFE is strongly expressed by liver macrophages and intestinal crypt cells, which behave as though they are relatively iron-deficient in HH. These latter observations suggest, paradoxically, that expression of wild-type HFE may lead to iron accumulation in these specialized cell types. Here we show that wild-type HFE protein raises cellular iron by inhibiting iron efflux from the monocytemacrophage cell line THP-1, and extend these results to macrophages derived from healthy individuals and HH patients. In addition, we find that the HH-associated mutant H41D has lost the ability to inhibit iron release despite binding to TfR1 as well as wild-type HFE. Finally, we show that the ability of HFE to block iron release is not competitively inhibited by transferrin. We conclude that HFE has two mutually exclusive functions, binding to TfR1 in competition with Tf, or inhibition of iron release. |
| first_indexed | 2024-03-07T02:33:32Z |
| format | Journal article |
| id | oxford-uuid:a8075516-ec1a-4062-bfaa-0555ffe1cede |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:33:32Z |
| publishDate | 2002 |
| record_format | dspace |
| spelling | oxford-uuid:a8075516-ec1a-4062-bfaa-0555ffe1cede2022-03-27T02:58:36ZThe hemochromatosis protein HFE inhibits iron export from macrophages.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a8075516-ec1a-4062-bfaa-0555ffe1cedeEnglishSymplectic Elements at Oxford2002Drakesmith, HSweetland, ESchimanski, LEdwards, JCowley, DAshraf, MBastin, JTownsend, AHereditary hemochromatosis (HH) is a disorder of iron metabolism caused by common mutations in the gene HFE. The HFE protein binds to transferrin receptor-1 (TfR1) in competition with transferrin, and in vitro, reduces cellular iron by reducing iron uptake. However, in vivo, HFE is strongly expressed by liver macrophages and intestinal crypt cells, which behave as though they are relatively iron-deficient in HH. These latter observations suggest, paradoxically, that expression of wild-type HFE may lead to iron accumulation in these specialized cell types. Here we show that wild-type HFE protein raises cellular iron by inhibiting iron efflux from the monocytemacrophage cell line THP-1, and extend these results to macrophages derived from healthy individuals and HH patients. In addition, we find that the HH-associated mutant H41D has lost the ability to inhibit iron release despite binding to TfR1 as well as wild-type HFE. Finally, we show that the ability of HFE to block iron release is not competitively inhibited by transferrin. We conclude that HFE has two mutually exclusive functions, binding to TfR1 in competition with Tf, or inhibition of iron release. |
| spellingShingle | Drakesmith, H Sweetland, E Schimanski, L Edwards, J Cowley, D Ashraf, M Bastin, J Townsend, A The hemochromatosis protein HFE inhibits iron export from macrophages. |
| title | The hemochromatosis protein HFE inhibits iron export from macrophages. |
| title_full | The hemochromatosis protein HFE inhibits iron export from macrophages. |
| title_fullStr | The hemochromatosis protein HFE inhibits iron export from macrophages. |
| title_full_unstemmed | The hemochromatosis protein HFE inhibits iron export from macrophages. |
| title_short | The hemochromatosis protein HFE inhibits iron export from macrophages. |
| title_sort | hemochromatosis protein hfe inhibits iron export from macrophages |
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