Journal
BLOOD CELLS MOLECULES AND DISEASES
Volume 40, Issue 1, Pages 132-138Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bcmd.2007.07.009
Keywords
liver; iron regulation; pro-hepcidin; pulse-chase study; metabolic protein labeling
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Funding
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK065029] Funding Source: NIH RePORTER
- NIDDK NIH HHS [R01 DK065029-01A1, R01 DK065029-02, R01 DK065029, R01 DK065029-03] Funding Source: Medline
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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.
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