Interaction of the Hereditary Hemochromatosis Protein HFE with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression

Gao, Junwei; Chen, Juxing; Kramer, Maxwell; Tsukamoto, Hidekazu; Zhang, An Sheng; Enns, Caroline A.

doi:10.1016/j.cmet.2009.01.010

Cited by 264 publications

(272 citation statements)

References 56 publications

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“…Both direct and indirect evidence points to the importance of the HFE/TfR2/Tf complex in the regulation of hepcidin. 37 Mice lacking functional Hfe or Tfr2 have a blunted hepcidin response in comparison to wild-type mice with a comparable iron load. 25,26 In the present study, we used an AAV2/8 vector to express either Hfe or Tfr2 under the control of a hepatocytespecific promoter.…”

Section: Discussionmentioning

confidence: 99%

“…A normal level of hepcidin expression requires the presence of both Hfe and Tfr2. 25,26,37,41 Overexpression of one in the absence of the other should be unable to correct for the lower hepcidin expression. To test this model, TfR2 245x/245x mice were injected with AAV-Hfe or AAV-c virus.…”

Section: Tfr2 and Hfe Individually Are Insufficient To Change The Ementioning

confidence: 99%

“…34 TfR2 and HFE are capable of forming a complex, 35,36 suggesting that the complex is involved in hepcidin regulation. 37 In this study, we used a recombinant serotype 2 adenoassociated virus vector pseudotyped with serotype 8 capsid (AAV2/8) and carrying a hepatic-specific promoter 38 to express either Hfe or Tfr2 in mice to test the role of the HFE/TfR2 complex in the regulation of hepcidin. Our results indicate that the virally encoded Hfe and Tfr2 are expressed in mouse livers.…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

Gao

Chen

Domenico

et al. 2010

Blood

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Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrinreceptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for regulation of hepcidin expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe and hepcidin mRNA and lowered hepatic iron and Tf saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron levels. Expression of Hfe in wild-type mice increased hepcidin mRNA and lowered iron levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in formation of the Hfe/Tfr2 complex that regulates hepcidin expression. In addition, these studies show that the use of recombinant AAV vector to deliver genes is a promising approach for studying physiologic consequences of protein complexes. (Blood. 2010;115(16):3374-3381) IntroductionHereditary hemochromatosis (HH) is an autosomal recessive disease of iron metabolism characterized by increased intestinal iron absorption and hepatic iron overload. 1 HH is caused by mutations in genes encoding proteins involved in iron homeostasis, including the HH protein, HFE 2 ; hemojuvelin 3 ; hepcidin 4 ; transferrin-receptor 2 (TfR2) 5 ; and ferroportin. 6 Accumulation of excessive iron results in hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, arrhythmias, diabetes, arthritis, and hypogonadotropic hypogonadism. 7 HH type 1, the most common form of HH, is caused by a missense mutation in HFE resulting in a C282Y (numbering system includes the first 23 amino acid signal peptide) substitution and accounts for 85% of HH. 2 HFE encodes an atypical major histocompatibility complex class I protein. Like the major histocompatibility complex class I proteins, HFE is a membrane protein that consists of a signal sequence, ␣1-␣3 domains followed by a transmembrane domain, and a short cytoplasmic domain. HFE also forms a heterodimeric complex with ␤2-microglobulin. 8 The C282Y mutation in HFE disrupts a disulfide bond in the ␣3 domain, leading to misfolding, lack of association with ␤2-microglobulin, and failure to traffic to the cell surface. 9 The Hfe knockout mouse (Hfe Ϫ/Ϫ ) also develops iron overload, confirming that the HFE-C282Y mutation confers loss of rather than gain of function. 10 Although the importance of HFE in iron regulation is apparent in patients with HH and murine models, 10,11 the underlying mechanism by which HFE regulates iron metabolism is only beginning to be understood.Type 3 HH is caused by a variety o...

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Section: Discussionmentioning

confidence: 99%

Section: Tfr2 and Hfe Individually Are Insufficient To Change The Ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

Gao

Chen

Domenico

et al. 2010

Blood

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“…The TfR2 protein is a transmembrane homodimer homolog of TfR1 and it is mainly expressed in the liver [21]. It is thought that TfR2 binds to HFE at cell surface and acts as a body iron sensor of diferric transferrin, resulting in the upregulation of hepcidin production through a not yet fully understood signalling pathway [22][23][24][25]. Concerning the novel variants in TfR2, in the case of p.Leu750Pro, proline is more hydrophilic than leucine and gives rise to a less flexible protein.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Faria

Silva

et al. 2016

Blood Cells, Molecules, and Diseases

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Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron absorption resulting in pathologically increased body iron stores. It is typically associated with common HFE gene mutation (p.Cys282Tyr and p.His63Asp). However, in Southern European populations up to one third of HH patients do not carry the risk genotypes. This study aimed to explore the use of next-generation sequencing (NGS) technology to analyse a panel of iron metabolism-related genes (HFE, TFR2, HJV, HAMP, SLC40A1, and FTL) in 87 non-classic HH Portuguese patients. A total of 1241 genetic alterations were detected corresponding to 53 different variants, 13 of which were not described in the available public databases. Among them, five were predicted to be potentially pathogenic: three novel mutations in TFR2 [two missense (p.Leu750Pro and p.Ala777Val) and one intronic splicing mutation (c.967-1G NC)], one missense mutation in HFE (p.Tyr230Cys), and one mutation in the 5′-UTR of HAMP gene (c. -25GN A). The results reported here illustrate the usefulness of NGS for targeted iron metabolism-related gene panels, as a likely cost-effective approach for molecular genetics diagnosis of non-classic HH patients. Simultaneously, it has contributed to the knowledge of the pathophysiology of those rare iron metabolism-related disorders.

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“…Hepcidin binds to ferroportin, an iron efflux channel expressed in intestinal epithelium, hepatocytes, and macrophages, thereby promoting ferroportin degradation, so that iron export is prevented (16,17). Regulation of hepcidin transcription by hepatocytes required HFE to form a complex with transferrin receptor 2, not TfR1, a switch mediated by holo-Tf, which displaces HFE from TfR1 due to its greater affinity (18,19).…”

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confidence: 99%

Ubiquitination of lysine-331 by Kaposi's sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation

Rhodes

Boyle

Boname

et al. 2010

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

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The nonclassical MHC class I-related (MHC-I) molecule HFE controls cellular iron homeostasis by a mechanism that has not been fully elucidated. We examined the regulation of HFE by K5, the E3 ubiquitin ligase encoded by Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8), that is known to down-regulate classical MHC-I. K5 down-regulated HFE efficiently, using polyubiquitination of the membrane proximal lysine in the HFE cytoplasmic tail (K331), to target the molecule for degradation via ESCRT1/TSG101-dependent sorting from endosomes to multivesicular bodies (MVBs)/lysosomes. In the primary effusion lymphoma cell line BC-3, which carries latent KSHV, HFE was degraded rapidly upon virus reactivation. HFE was ubiquitinated on lysine-331 in unactivated BC-3 cells, conditions where K5 was not detectable, consistent with an endogenous E3 ubiquitin ligase controlling HFE expression. The results show regulated expression of HFE by ubiquitination, consistent with a role in cellular iron homeostasis, a molecular mechanism targeted by KSHV to achieve a positive iron balance.

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Interaction of the Hereditary Hemochromatosis Protein HFE with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression

Cited by 264 publications

References 56 publications

Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Ubiquitination of lysine-331 by Kaposi's sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation

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