Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin
Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin
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DOI：
10.1016/j.bcmd.2007.07.009
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发表时间：
2008-01-01
影响因子：
2.3
通讯作者：
Ganz, Tomas
中科院分区：
文献类型：
--
作者：
Valore, Enka V.;Ganz, Tomas
Hepcidin编码为84个氨基酸的前肽，含有典型的n端24个氨基酸的内质网靶向信号序列。和一个35个氨基酸的前区（pro），具有一致的furin切割位点，紧接着是c端25个氨基酸的生物活性铁调节激素（成熟肽）。我们在人肝癌HepG2细胞和骨形态发生蛋白（BMP-9）诱导的人原代肝细胞中进行了hepcidin翻译后加工的脉冲追踪研究。在一些实验中，用呋喃蛋白酶抑制剂decanoyl- arg - valys - arg - arg -氯甲基酮（CMK）或呋喃siRNA处理细胞。在没有furin抑制剂的情况下，hepcidin被发现在少于1it的时间内加工，并以3kda的形式分泌，与抗成熟抗体反应，但不与抗pro抗体反应。在furin抑制剂或furin siRNA存在的情况下，与抗亲抗体和抗成熟抗体反应的6kda形式被迅速分泌到培养基中。缺氧诱导因子（HIF）途径抑制剂或30 μ M全转铁蛋白或载铁转铁蛋白处理不影响加工。总之，肝激素原转化酶furin介导了hepcidin的翻译后加工。转铁蛋白或HIF途径不调节hepcidin的蛋白水解裂解。(C) 2007爱思唯尔公司版权所有。
Hepcidin is encoded as an 84 amino acid prepropeptide containing a typical N-terminal 24 amino acid endoplasmic reticulum targeting signal sequence. and a 35 amino acid proregion (pro) with a consensus furin cleavage site immediately followed by the C-terminal 25 amino acid bioactive iron-regulatory hormone (mature peptide). We performed pulse-chase studies of posttranslational processing of hepcidin in human hepatoma HepG2 cells and in primary human hepatocytes induced with bone morphogenic protein (BMP-9). In some experiments, the cells were treated with the furin protease inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone (CMK) or furin siRNA. In the absence of furin inhibitor, hepcidin was found to be processed in less than I It and secreted as a 3 kDa form reactive with anti-mature but not anti-pro antibody. In the presence of furin inhibitors or furin siRNA, a 6 kDa form reactive with both anti-pro and anti-mature antibody was rapidly secreted into the medium. Processing was not affected by inhibitors of the hypoxia inducible factor (HIF) pathway, or by treatment with 30 mu M holo- or apo-transferrin. In conclusion, the hepatic prohormone convertase furin mediates the posttranslational processing of hepcidin. The proteolytic cleavage of prohepcidin to hepcidin is not regulated by iron-transferrin or the HIF pathway. (C) 2007 Elsevier Inc. All rights reserved.