RETRACTED ARTICLE: Binding to the transferrin receptor is required for endocytosis of HFE and regulation of iron homeostasis

Ramalingam, T.; West, Anthony P.; Lebrón, José Antonio; Nangiana, Jasvinder; Hogan, Thomas H.; Enns, Caroline A.; Björkman, Pamela J.

doi:10.1038/35046611

Cited by 47 publications

(52 citation statements)

References 29 publications

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confidence: 72%

“…The high-affinity binding of HFE with TfR1 suggested that HFE-TfR1 complex formation might be important for the function of HFE protein in iron homeostasis (18)(19)(20)(21)(22)(23)(24)(25)(26). This hypothesis was supported by the observation that the transport of HFE to endosomes and the regulation of intracellular iron absorption in some cell lines depend on its association with TfR1 (27).Several studies on the interaction of HFE with TfR1 in transfected cell lines have attempted to characterize the biological effect of this interaction on iron homeostasis (22,23,(27)(28)(29)(30)(31). Several groups have reported that HeLa cells overexpressing HFE protein showed a decrease in ferritin level, an increase in TfR1, and an increase in iron regulatory protein activity, indicating lower levels of iron stores in the cells (22,23,30).…”

mentioning

confidence: 59%

“…Several studies on the interaction of HFE with TfR1 in transfected cell lines have attempted to characterize the biological effect of this interaction on iron homeostasis (22,23,(27)(28)(29)(30)(31). Several groups have reported that HeLa cells overexpressing HFE protein showed a decrease in ferritin level, an increase in TfR1, and an increase in iron regulatory protein activity, indicating lower levels of iron stores in the cells (22,23,30).…”

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confidence: 99%

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Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Waheed

Grubb

Zhou

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

124

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The protein defective in hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins and associates with ␤2-microglobulin (␤2M). Its association with ␤2M was previously shown to be necessary for its stability, normal intracellular processing, and cell surface expression in transfected COS cells. Here we use stably transfected Chinese hamster ovary cell lines expressing both HFE and ␤ 2 M or HFE alone to study the effects of ␤ 2 M on the stability and maturation of the HFE protein and on the role of HFE in transferrin receptor 1 (TfR1)-mediated iron uptake. In agreement with prior studies on other cell lines, we found that overexpression of HFE, without overexpressing ␤2M, resulted in a decrease in TfR1-dependent iron uptake and in lower iron levels in the cells, as evidenced by ferritin and TfR1 levels measured at steady state. However, overexpression of both HFE and ␤2M had the reverse effect and resulted in an increase in TfR1-dependent iron uptake and increased iron levels in the cells. The HFE-␤2M complex did not affect the affinity of TfR1 for transferrin or the internalization rate of transferrin-bound TfR1. Instead, HFE-␤2M enhanced the rate of recycling of TfR1 and resulted in an increase in the steady-state level of TfR1 at the cell surface of stably transfected cells. We propose that Chinese hamster ovary cells provide a model to explain the effect of the HFE-␤2M complex in duodenal crypt cells, where the HFE-␤2M complex appears to facilitate the uptake of transferrin-bound iron to sense the level of body iron stores. Impairment of this process in duodenal crypt cells leads them to be iron poor and to signal the differentiating enterocytes to take up iron excessively after they mature into villus cells in the duodenum of hereditary hemochromatosis patients.H ereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, characterized by excessive absorption of dietary iron in the small intestine. The excess iron is stored in the parenchymal cells of major tissues, primarily the liver, pancreas, heart, pituitary, and joints, eventually leading to severe tissue damage (1-3). The pathogenesis of HH is thought to involve a defect in the mechanism controlling iron absorption in the small intestine (4).The gene defective in hemochromatosis, HFE, encodes an MHC class I-type protein (5). In multiple population studies, 85-90% of HH patients of northern European ancestry were found to be homozygous for the C282Y mutation in HFE. About 5% are compound heterozygotes for C282Y and a second mutation, H63D (5-10). Even earlier, the observation that ␤ 2 -microglobulin (␤ 2 M)-deficient mice develop progressive iron overload similar to that seen in HH patients suggested the involvement of an MHC class I protein in HH (11, 12). Confirmation that mutations in HFE cause HH was provided by observations of mice with targeted disruption of the HFE gene. These HFE knockout mice showed high transferrin saturation and an increase in iron storage in hepatocytes (13-15).The C282Y mutati...

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supporting

confidence: 72%

mentioning

confidence: 59%

mentioning

confidence: 99%

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Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Waheed

Grubb

Zhou

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

124

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“…Wild-type HFE is associated closely with ␤ 2 M, and TfR1 and is expressed on the cell surface and in the TfR1-containing endosomes (29)(30)(31)(32)(33). A number of experiments have been undertaken in which wild-type HFE was overexpressed in cultured cells and the overexpressed wild-type HFE decreased transferrin-bound iron uptake (32)(33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse

Trinder

Olynyk

Sly

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary hemochromatosis (HH) is a disorder of iron metabolism in which enhanced iron absorption of dietary iron causes increased iron accumulation in the liver, heart, and pancreas. Most individuals with HH are homozygous for a C282Y mutation in the HFE gene. The function of HFE protein is unknown, but it is hypothesized that it acts in association with ␤2-microglobulin and transferrin receptor 1 to regulate iron uptake from plasma transferrin by the duodenum, the proposed mechanism by which body iron levels are sensed. The aim of this study was to test this hypothesis by comparing clearance of transferrin-bound iron in Hfe knockout (KO) mice with that observed in C57BL͞6 control mice. The mice were fed either an iron-deficient, control, or iron-loaded diet for 6 weeks to alter body iron status. The mice then were injected i.v. with 59 Fe-transferrin, and blood samples were taken over 2 h to determine the plasma 59 Fe turnover. After 2 h, the mice were killed and the amount of radioactivity in the duodenum, liver, and kidney was measured. In both Hfe KO and C57BL͞6 mice, plasma iron turnover and iron uptake from plasma transferrin by the duodenum, liver, and kidney correlated positively with plasma iron concentration. However, duodenal iron uptake from plasma transferrin was decreased in the Hfe KO mice compared with the control mice. Despite this difference in duodenal uptake, the Hfe KO mice showed no decrease in iron uptake by the liver and kidney or alteration in the plasma iron turnover when compared with C57BL͞6 mice. These data support the hypothesis that HFE regulates duodenal uptake of transferrin-bound iron from plasma, and that this mechanism of sensing body iron status, as reflected in plasma iron levels, is impaired in HH.

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“…By using physiological systems and heterologous expression systems, several groups have begun to characterize the role of HFE in cellular iron uptake (2)(3)(4)(5)(6)(7)(8)(9), with the latest contribution by Schwake et al, the current article in focus (Ref. 10, see p. C973 in this issue).…”

mentioning

confidence: 99%

Focus on “Regulation of transferrin-induced endocytosis by wild-type and C282Y-mutant HFE in transfected HeLa cells”

Okamoto

2002

American Journal of Physiology-Cell Physiology

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RETRACTED ARTICLE: Binding to the transferrin receptor is required for endocytosis of HFE and regulation of iron homeostasis

Cited by 47 publications

References 29 publications

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse

Focus on “Regulation of transferrin-induced endocytosis by wild-type and C282Y-mutant HFE in transfected HeLa cells”

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