ライフサイエンスコーパス: HJV

1 ly attenuated in the absence of hemojuvelin (Hjv).

2 g in hh are hepcidin (HAMP) and hemojuvelin (HJV).

3 modulated by the BMP coreceptor hemojuvelin (HJV).

4 r of hepatic hepcidin expression and cleaves HJV.

5 presses hepcidin expression independently of HJV.

6 e examined the trafficking and processing of HJV.

7 uscle and liver could be the source of serum HJV.

8 We suggest that it be designated HJV.

9 critical for the iron regulatory function of HJV.

10 gosaccharides to complex oligosaccharides on HJV.

11 exerts its inhibitory effect by inactivating HJV.

12 8), which produces one major soluble form of HJV.

13 s HJV, leading to a decrease in cell surface HJV.

14 deficient for both Tmprss6 and hemojuvelin (Hjv), a BMP coreceptor that augments hepcidin expression

15 hepcidin production by cleaving Hemojuvelin (Hjv), a key modulator of hepcidin expression, from the h

16 dies demonstrate that neogenin may stabilize HJV, a glycosylphosphatidylinositol-anchored protein tha

17 Cellular HJV acts as a BMP co-receptor to enhance the transcripti

18 Membrane-anchored HJV acts as a coreceptor for bone morphogenetic proteins

19 iron overload similar to mice deficient for Hjv alone.

20 eficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2.

21 HJV also binds neogenin, a membrane protein widely expre

22 HJV also interacts with neogenin, a ubiquitously express

23 Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C,

24 ons in the recently cloned hemojuvelin gene (HJV; also called HFE2), whereas Type 2B HH is caused by

25 Hemojuvelin (HJV; also called repulsive guidance molecule c, RGMC) is

26 iron homeostasis via inhibiting secretion of HJV, an inhibitor of BMP signaling, to enhance BMP signa

27 neogenin interacted with MT2 as well as with HJV and facilitated the cleavage of HJV by MT2.

28 93 cells and characterized the processing of HJV and its effect on iron homeostasis.

29 Both HJV and neogenin were expressed in liver hepatocytes.

30 ctRIIA, Bmpr2, Hfe, and, to a lesser extent, Hjv and Tfr2.

31 independently of each other, we intercrossed Hjv(-/-) and Bmp6(-/-) mice and compared the phenotype o

32 Both hemojuvelin (HJV) and bone morphogenic protein-6 (BMP6) are essential

33 Cells co-transfected with hemojuvelin (HJV) and matriptase-2 (MT-2) were used as a model to inv

34 Hemojuvelin (HJV) and matriptase-2 (MT2) are co-expressed in hepatocy

35 m iron challenge in iron-depleted Hfe, Tfr2, Hjv, and Bmp6 mutant mice.

36 Mutations in HFE, HJV, and TfR2 cause autosomal-recessive forms of hemochr

37 ic BMP6 expression by iron is independent of HJV, and that expression of HJV in hepatocytes plays an

38 Soluble HJV antagonizes bone morphogenetic protein signaling and

39 Mutations in HJV are implicated in the majority of diagnosed juvenile

40 rine hepcidin, because these molecules, like Hjv, are known to be involved in hepcidin signaling.

41 gh a receptor complex requiring hemojuvelin (HJV) as a co-receptor.

42 BMPs), apparently by binding to hemojuvelin (Hjv) as a coreceptor and signaling through Smad4.

43 sent work, we show that matriptase-2 cleaves HJV at Arg(288), which produces one major soluble form o

44 in forms a ternary complex with both MT2 and HJV at the plasma membrane.

45 ntrations transmitted through HFE, TfR2, and HJV augment BMP receptor sensitivity to BMPs.

46 ng complex oligosaccharides, indicating that HJV avoided Golgi processing.

47 t a model in which retrograde trafficking of HJV before cleavage is the predominant processing pathwa

48 HJV binds BMP6 and increases hepcidin expression presuma

49 vivo studies validated the important role of HJV-BMP interaction for Hjv stimulation of BMP signaling

50 mechanism underlying neogenin regulation of HJV-BMP signaling.

51 as a scaffold to facilitate assembly of the HJV.BMP.BMP receptor complex to induce hepcidin expressi

52 TfR2, HJV, BMP6, and, to a lesser extent, HFE are required for

53 Surprisingly, although cleavage of HJV by furin has been implicated in the regulation of HJ

54 lso been shown to facilitate the cleavage of HJV by furin in transfected cells.

55 as with HJV and facilitated the cleavage of HJV by MT2.

56 HJV can be cleaved by the furin family of proprotein con

57 Crystallography studies indicate that HJV can simultaneously bind to both BMP2 and the ubiquit

58 While HJV can use all 3 BMP type I receptors (ALK2, ALK3, and

59 These studies confirm that mutations in HJV cause juvenile hemochromatosis.

60 ne encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low h

61 Mutations in hemojuvelin (HJV) cause severe, early-onset juvenile hemochromatosis.

62 In this study, we stably transfected HJV cDNA into human embryonic kidney 293 cells and chara

63 The complex facilitates HJV cleavage by MT2, and release of the cleaved HJV from

64 HJV co-immunoprecipitated with neogenin, a receptor invo

65 nistration of a recombinant, soluble form of HJV decreased hepcidin expression and increased serum ir

66 Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or

67 We also examined the impact of Bmp6 and/or Hjv deletion on the regulation of hepcidin by inflammati

68 Hemojuvelin (HJV), encoded by the gene HFE2, is a critical upstream r

69 cholesterol depletion by filipin blocks both HJV endocytosis and HJV release suggest that neogenin-me

70 of cellular HJV release, and stimulation of HJV-enhanced hepcidin expression.

71 ors ActRIIA and BMPRII, but not ActRIIB, and HJV enhances utilization of ActRIIA by BMP-2 and BMP-4.

72 4-induced hepcidin mRNA levels by 16-fold in HJV-expressing HepG2 cells but only by about 2-fold in c

73 In contrast to MT2, increased Hjv expression caused no significant changes in wild-typ

74 HJV expression is detected in hepatocytes, as well as in

75 e demonstrate a physical interaction between HJV.Fc and BMP6, and we show that BMP6 increases hepcidi

76 pression in vitro and that administration of HJV.Fc decreases hepcidin expression, increases ferropor

77 In vivo, HJV.Fc or a neutralizing antibody to BMP6 inhibits hepci

78 We also show that soluble hemojuvelin (HJV.Fc) selectively inhibits BMP induction of hepcidin e

79 show that compared with soluble hemojuvelin (HJV.Fc), the homologous DRAGON.Fc is a more potent inhib

80 These data suggest that, in Hjv(-/-) females, Bmp6 can provide a signal adequate to

81 cting as a decoy that competes with membrane HJV for BMP ligands.

82 s required for the processing and release of HJV from cells.

83 nizes hepcidin induction by BMPs by cleaving HJV from the cell membrane.

84 cleavage by MT2, and release of the cleaved HJV from the cell occurs after a retrograde trafficking

85 rin has been implicated in the regulation of HJV function in cell culture models and furin-cleaved so

86 In addition, the HJV G320V mutant implicated in Type 2A HH did not co-imm

87 We have disrupted the murine Hjv gene and shown that Hjv-/- mice have markedly increa

88 nsferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes.

89 We have identified novel mutations in HJV, HAMP, and SLC40A1 in countries not normally associa

90 HJV has also been demonstrated to bind to neogenin, but

91 This shed form of HJV has decreased ability to bind BMP6 and does not supp

92 Patients with HJV hemochromatosis have low urinary levels of hepcidin,

93 e three hemochromatosis-associated proteins: HJV (hemojuvelin), HFE (hemochromatosis protein), and Tf

94 The protein product of HJV, hemojuvelin, contains a C-terminal glycosylphosphat

95 Hemojuvelin (HJV), HFE, and transferrin receptor-2 (TfR2) facilitate

96 in as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for th

97 ad in PCT, we compared sequences of HAMP and HJV in 96 patients with PCT and 88 HFE C282Y homozygotes

98 MT2 regulates the levels of membrane-bound HJV in hepatocytes by binding to and cleaving HJV into a

99 Expression of HJV in hepatocytes of Hjv(-/-) mice using an AAV2/8 vect

100 s independent of HJV, and that expression of HJV in hepatocytes plays an essential role in hepcidin e

101 BMP-4, and BMP-6 are endogenous ligands for HJV in hepatoma-derived cell lines, and that all 3 of th

102 er the stimulation of hepcidin expression by Hjv in mice.

103 Expression of this mutant Hjv in the liver of Hjv(-/-) mice dramatically attenuate

104 We characterized the role of hepatocyte HJV in the regulation of BMP6 and hepcidin expression.

105 6 (BMP6) or the BMP coreceptor hemojuvelin (HJV) in mice leads to a similar phenotype with hepcidin

106 Secreted HJV, in contrast, has complex oligosaccharides and can b

107 pound heterozygous mutations in hemojuvelin (HJV), including a termination codon, in a patient with j

108 Finally, we show that HJV-induced BMP signaling and hepcidin expression are no

109 55Fe accumulation studies indicated that the HJV-induced increase in intracellular iron levels in hum

110 However, the role of the neogenin-HJV interaction in the function of HJV is unknown.

111 ue to the inhibition of cell surface MT2 and HJV internalization.

112 JV in hepatocytes by binding to and cleaving HJV into an inactive soluble form that is released from

113 HJV is a bone morphogenetic protein (BMP) coreceptor and

114 is is consistent with the current views that HJV is a coreceptor for BMP6 in hepatocytes.

115 HJV is a glycosylphosphatidylinositol-linked membrane pr

116 Our results indicate that HJV is a glycosylphosphatidylinositol-linked protein and

117 Previous studies demonstrated that HJV is a GPI-anchored protein, binds the proteins neogen

118 ell culture models and furin-cleaved soluble Hjv is detectable in the serum of mice, mutating the fur

119 smembrane domains of Hfe are sufficient, and Hjv is essential, for Hfe-mediated induction of hepcidin

120 diated induction of hepcidin expression when HJV is expressed.

121 HJV is highly expressed in both skeletal muscle and live

122 t changes in wild-type mice, suggesting that Hjv is not a limiting factor for hepcidin expression.

123 The normal function of HJV is unknown.

124 neogenin-HJV interaction in the function of HJV is unknown.

125 Hemojuvelin (HJV) is a coreceptor for bone morphogenetic protein (BMP

126 Hemojuvelin (HJV) is a glycosylphosphatidylinositol-linked protein an

127 Hemojuvelin (HJV) is an important regulator of iron metabolism.

128 Its encoded protein, hemojuvelin (HJV), is a co-receptor for the bone morphogenetic protei

129 RGMc, also called hemojuvelin (HJV), is essential for iron homeostasis.

130 Similarly, RPE cells from hemojuvelin (Hjv)-knockout mice, another model of hemochromatosis, al

131 ndicate that matriptase-2 binds and degrades HJV, leading to a decrease in cell surface HJV.

132 To determine whether BMP6 and HJV may also signal to hepcidin independently of each ot

133 These results demonstrate that recombinant HJV may be a useful therapeutic agent for treatment of t

134 Thus, HJV-mediated BMP signaling and hepcidin regulation occur

135 Furthermore, iron depletion in Hjv(-/-) mice decreased hepatic BMP6 mRNA.

136 Unlike wild-type mice, Hjv(-/-) mice developed lethal plague when challenged wi

137 These results indicate that Hjv(-/-) mice do not lack BMP6.

138 xpression of this mutant Hjv in the liver of Hjv(-/-) mice dramatically attenuated its induction of B

139 ling and hepcidin expression in the liver of Hjv(-/-) mice of both sexes, and led to iron accumulatio

140 Expression of HJV in hepatocytes of Hjv(-/-) mice using an AAV2/8 vector, increased hepatic

141 Immunization of Hjv(-/-) mice with a subunit vaccine that blocks Y. pest

142 In Hjv(-/-) mice, increased expression of exogenous MT2 in

143 crease of hepcidin was seen in Bmp6(-/-) and Hjv(-/-) mice.

144 In HJV-null (Hjv(-/-)) mice that have severe iron overload and marked

145 We used hemojuvelin-knockout (Hjv(-/-)) mice to examine whether iron-storage disease r

146 disrupted the murine Hjv gene and shown that Hjv-/- mice have markedly increased iron deposition in l

147 Hepcidin mRNA expression was decreased in Hjv-/- mice.

148 mice showed nearly no increase, and Tfr2 and Hjv mutant mice showed no increase in hepcidin expressio

149 e morphogenetic protein (BMP) coreceptor and HJV mutants have impaired BMP signaling.

150 ogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surfa

151 Together, these results suggest that the HJV-neogenin interaction is required for the BMP-mediate

152 her studies indicated that disruption of the HJV-neogenin interaction is responsible for a marked sup

153 In HJV-null (Hjv(-/-)) mice that have severe iron overload

154 odels of hemochromatosis (HFE-null mouse and HJV-null mouse) and in two nongenetic models of iron ove

155 n with siRNA increased the amount of MT2 and HJV on the plasma membrane, suggesting a lack of neogeni

156 involved either in retrograde trafficking of HJV or in cleavage leading to HJV release.

157 usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP).

158 transferrin receptor 2 (Tfr2), hemojuvelin (HJV), or bone morphogenetic protein 6 (BMP6) prevent app

159 e to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand c

160 Cellular HJV reached the plasma membrane without obtaining comple

161 ng that knock-down of endogenous neogenin, a HJV receptor, in C2C12 cells suppresses HJV shedding and

162 udy we characterized the role of neogenin in HJV-regulated hepcidin expression.

163 Hemojuvelin (HJV) regulates iron homeostasis by direct interaction wi

164 n of endogenous neogenin markedly suppresses HJV release but has no evident effect on HJV trafficking

165 The additional findings that HJV release is coupled to lysosomal degradation of neoge

166 d HJV release suggest that neogenin-mediated HJV release occurs after the HJV-neogenin complex is int

167 n by filipin blocks both HJV endocytosis and HJV release suggest that neogenin-mediated HJV release o

168 ssesses two functions, mediation of cellular HJV release, and stimulation of HJV-enhanced hepcidin ex

169 ogenin ectodomain to cells markedly inhibits HJV release, indicating that the HJV shedding is not pro

170 trafficking of HJV or in cleavage leading to HJV release.

171 nations of BMP ligands and receptors used by HJV remain unknown.

172 Release of HJV requires it to bind to the transmembrane receptor ne

173 FE2), which encodes the protein hemojuvelin (HJV), result in the absence of hepcidin and an early-ons

174 n hemojuvelin/repulsive guidance molecule c (HJV/RGMc) cause juvenile hemochromatosis (JH), a rapidly

175 are seen in Hfe(-/-) RPE cells as well as in Hjv(-/-) RPE cells, providing a molecular basis for the

176 hyperproliferative phenotype of Hfe(-/-) and Hjv(-/-) RPE cells.

177 al role in iron homeostasis by regulation of HJV secretion and bone morphogenetic protein (BMP) signa

178 We demonstrate in vitro that HJV selectively uses the BMP type II receptors ActRIIA a

179 up-regulation of TMPRSS6 increases membrane HJV shedding and decreases hepcidin promoter responsiven

180 n, a HJV receptor, in C2C12 cells suppresses HJV shedding and that overexpression of neogenin in HEK2

181 ith the observations in iron-deficient rats, HJV shedding in these cell lines was down-regulated by h

182 nhances this process, suggests that membrane HJV shedding is mediated by neogenin.

183 ly inhibits HJV release, indicating that the HJV shedding is not processed before trafficking to the

184 or its antagonist, noggin, was able to alter HJV shedding support the lack of involvement of BMP sign

185 uman hepatoma cell line) cells showed active HJV shedding, implying that both skeletal muscle and liv

186 significance and the underlying mechanism of HJV shedding.

187 he important role of HJV-BMP interaction for Hjv stimulation of BMP signaling and hepcidin expression

188 cted with either empty vector or G99V mutant HJV that does not bind BMPs.

189 Here we identify a mutation in HJV that specifically lowers its interaction with neogen

190 onvertases, which releases a soluble form of HJV that suppresses BMP signaling and hepcidin expressio

191 results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intra

192 Neogenin does not, however, play a role in HJV trafficking to the cell surface, suggesting that it

193 ses HJV release but has no evident effect on HJV trafficking to the plasma membrane.

194 The role that neogenin plays in HJV trafficking was investigated, using HepG2 cells, a h

195 Membrane-anchored HJV up-regulates expression of the iron regulatory hormo

196 The increase in MT2 and HJV upon neogenin knockdown was likely due to the inhibi

197 ucing bone morphogenetic protein co-receptor HJV via inhibition of the membrane-bound serine protease

198 des showed that MT2 cleavage of cell surface HJV was coupled to a transition from high mannose oligos

199 Hemojuvelin (HJV) was recently identified as a critical regulator of

200 Two intronic polymorphisms in HJV were associated with elevated serum ferritin in HFE

201 nship, 2 previously undescribed mutations of HJV were identified, c.238T>C (C80R) and c.302T>C (L101P

202 of their interaction and the interaction of HJV with BMP-2.

203 ly suppressed by blocking the interaction of HJV with full-length neogenin with a soluble fragment of

204 lex oligosaccharides and can be derived from HJV with high-mannose oligosaccharides at the plasma mem

205 we detected an early phase increase of serum HJV with no significant change of either HFE2 mRNA or pr