Functional investigation of hemojuvelin in regulation of hepcidin expression

Summary

Principal Investigator: An Sheng Zhang
Affiliation: Oregon Health and Science University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Hereditary hemochromatosis (HH) is a heterogeneous group of inherited iron overload disorders leading to iron accumulation in specific organs, including the liver, heart, thymus, and pancreas. Excess iron in affected tissues catalyzes oxidative damage, resulting in cirrhosis, hepatoma, cardiomyopathy, diabetes, hypogonadotropic hypogonadism, and arthritis. Juvenile hemochromatosis (JH) is the most severe form of HH. It is an autosomal recessive disease with high penetrance that affects young patients of both sexes and leads to severe clinical complications typically in the teens and early 20s. If untreated, JH is lethal. A recent study identified the gene, named HFE2, which is responsible for the onset of disease in the majority of JH patients. Sequence analysis of HFE2 in JH patients revealed numerous homozygous or compound heterozygous mutations, including missense, frame shift, and nonsense mutations. Although the amino acid substitution G320V was found to account for about two-thirds of the cases, the sporadic distribution of these mutations hints that JH is due to the loss of HFE2 function. The importance of HFE2 in iron homeostasis has been confirmed by studies in HFE2-disrupted (Hjv-/-) mice, showing a severe iron overload phenotype similar to JH patients. Intriguingly, a severe depression of hepatic hepcidin expression was observed both in HFE2 mutation-related JH patients and in Hjv-/- mice, indicating that HFE2 is a key upstream regulator of hepcidin, a central iron regulatory hormone. Hepcidin is mainly expressed in liver hepatocytes. The protein encoded by HFE2, hemojuvelin (HJV), shares high sequence similarity to two repulsive guidance molecule (RGM) family members in mice (RGMa and b). A recent study found that HJV is a co-receptor for bone morphogenetic protein 2 and 4 (BMP2 and BMP4) and enhances BMP-induced hepcidin expression. Our preliminary results showed that HJV is a GPI-anchored protein, undergoes a partial autocatalytic cleavage and increases iron accumulation in HEK293 cells through its interaction with neogenin, a receptor for RGMa. Our study also indicates that neogenin is required for HJV release from the cells. We propose to: 1). Determine the role of neogenin in cellular HJV processing. 2). Examine the role of BMP and neogenin signaling in HJV-mediated hepcidin expression. 3). Characterize the role of serum HJV in body iron homeostasis. Knowledge gained regarding the function of neogenin and BMP signaling in HJV-mediated hepatic hepcidin expression could lead to understanding body iron homeostasis, as well as novel treatments for iron overload disorders. PUBLIC HEALTH RELEVANCE: Iron is an essential nutrient required for a variety of biochemical processes such as respiration, metabolism, and DNA synthesis, but also toxic when it is in excess (Bothwell et al., 1995). Hereditary hemochromatosis (HH), the most common inherited disease in Caucasians, is a heterogeneous group of inherited iron overload disorders (Cox, 1996;Hentze et al., 2004). Elucidation of the role of HFE2, the juvenile HH-causing gene (Papanikolaou et al., 2004), will lead to a full understanding of the regulation of body iron homeostasis as well as more effective cures for iron overload disorders.
Funding Period: ----------------2008 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 283:17494-502. 2008
  2. pmc Increased iron loading induces Bmp6 expression in the non-parenchymal cells of the liver independent of the BMP-signaling pathway
    Caroline A Enns
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR, USA
    PLoS ONE 8:e60534. 2013
  3. pmc Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage
    Caroline A Enns
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 287:35104-17. 2012
  4. pmc Iron regulation by hepcidin
    Ningning Zhao
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Clin Invest 123:2337-43. 2013
  5. pmc Use of Nramp2-transfected Chinese hamster ovary cells and reticulocytes from mk/mk mice to study iron transport mechanisms
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR, USA
    Exp Hematol 36:1227-35. 2008
  6. pmc Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 284:22580-9. 2009
  7. pmc Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells
    Julia E Maxson
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239, USA
    Blood 113:1786-93. 2009
  8. pmc Matriptase-2- and proprotein convertase-cleaved forms of hemojuvelin have different roles in the down-regulation of hepcidin expression
    Julia E Maxson
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 285:39021-8. 2010
  9. pmc Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
    Blood 117:1687-99. 2011
  10. pmc Iron homeostasis: recently identified proteins provide insight into novel control mechanisms
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 284:711-5. 2009

Scientific Experts

  • An Sheng Zhang
  • Caroline A Enns
  • Julia E Maxson
  • Ningning Zhao
  • Riffat Ahmed
  • Hidekazu Tsukamoto
  • Akiko Ueno
  • Christal Worthen
  • Jiaohong Wang
  • Juxing Chen

Detail Information

Publications12

  1. pmc Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 283:17494-502. 2008
    ....
  2. pmc Increased iron loading induces Bmp6 expression in the non-parenchymal cells of the liver independent of the BMP-signaling pathway
    Caroline A Enns
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR, USA
    PLoS ONE 8:e60534. 2013
    ..These observations suggest an important role of the non-parenchymal liver cells in regulating iron-homeostasis by acting as a source of Bmp6...
  3. pmc Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage
    Caroline A Enns
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 287:35104-17. 2012
    ..The complex facilitates HJV cleavage by MT2, and release of the cleaved HJV from the cell occurs after a retrograde trafficking through the TGN/Golgi compartments...
  4. pmc Iron regulation by hepcidin
    Ningning Zhao
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Clin Invest 123:2337-43. 2013
    ..Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload...
  5. pmc Use of Nramp2-transfected Chinese hamster ovary cells and reticulocytes from mk/mk mice to study iron transport mechanisms
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR, USA
    Exp Hematol 36:1227-35. 2008
    ....
  6. pmc Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 284:22580-9. 2009
    ..Combined with our previous studies, our results support that hepatic neogenin possesses two functions, mediation of cellular HJV release, and stimulation of HJV-enhanced hepcidin expression...
  7. pmc Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells
    Julia E Maxson
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239, USA
    Blood 113:1786-93. 2009
    ..Neogenin does not, however, play a role in HJV trafficking to the cell surface, suggesting that it could be involved either in retrograde trafficking of HJV or in cleavage leading to HJV release...
  8. pmc Matriptase-2- and proprotein convertase-cleaved forms of hemojuvelin have different roles in the down-regulation of hepcidin expression
    Julia E Maxson
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 285:39021-8. 2010
    ..These results suggest that the matriptase-2 and proprotein convertase-cleavage products have different roles in the regulation of hepcidin expression...
  9. pmc Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
    Blood 117:1687-99. 2011
    ..However, an increase in matriptase-2 protein in the liver from ID rats was detected, suggesting that suppression of hepcidin expression in response to acute iron deprivation is mediated by an increase in matriptase-2 protein levels...
  10. pmc Iron homeostasis: recently identified proteins provide insight into novel control mechanisms
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 284:711-5. 2009
    ..Disruption of these processes causes either iron-deficient anemia or iron overload disorders. In this minireview, we focus on the roles of recently identified proteins in the regulation of iron homeostasis...
  11. pmc The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo
    An Sheng Zhang
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA
    J Biol Chem 285:16416-23. 2010
    ....