Document Detail


Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin.
MedLine Citation:
PMID:  23390091     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The first seven members of the proprotein convertase (PC) family activate protein precursors by cleavage after basic residues. While PC7 has no known specific substrates, it shows redundancy with other PCs. A genome-wide association study suggested that circulating levels of shed human transferrin receptor 1 (hTfR1) are regulated by PC7. We thus examined whether hTfR1 constitutes a specific substrate for PC7. Coexpression of hTfR1 with PCs in several cell lines indicated that PC7 is the only convertase that sheds this receptor into the medium. Site-directed mutagenesis showed that cleavage occurs at the unusual site KTECER100 ↓LA, in which the P1 Arg100 and P6 Lys95 are critical. Pharmacological treatments revealed that shedding of hTfR1 by PC7 requires endocytosis into acidic clathrin-coated vesicles. A PC7 chimera, in which the transmembrane domain and the cytosolic tail of PC7 were replaced by that of the convertase furin, lost its ability to cleave the receptor, demonstrating the importance of these domains in the regulation of PC7 function. Analysis of primary hepatocytes from mice lacking furin, PC5, PACE4, or PC7 revealed that hepcidin, which limits iron availability in the circulation, is specifically generated by furin and not by PC7. Finally, depletion of iron in the medium of hepatoma cell lines incubated with the iron chelator desferrioxamine resulted in PC7 down-regulation. Conclusion: Among the PC family members, only furin activates hepcidin in hepatocytes, and uniquely the full-length membrane-bound PC7 can directly shed hTfR1 by cleavage at Arg100 ↓. Our results support the notion that, when iron is limiting, hTfR1 levels increase at least in part by way of the down-regulation of PC7 expression. (HEPATOLOGY 2013;).
Authors:
Johann Guillemot; Maryssa Canuel; Rachid Essalmani; Annik Prat; Nabil G Seidah
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-05-15
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  57     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-13     Completed Date:  2013-08-16     Revised Date:  2014-02-28    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2514-24     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD / metabolism*
Antimicrobial Cationic Peptides / metabolism*
COS Cells
Cercopithecus aethiops
Down-Regulation
Endosomes / metabolism
Furin / metabolism*
HEK293 Cells
Hep G2 Cells
Hepatocytes / metabolism*
Hepcidins
Humans
Iron / metabolism*
Mice
Protein Structure, Tertiary
Receptors, Transferrin / metabolism*
Subtilisins / metabolism*
Grant Support
ID/Acronym/Agency:
MOP-44363//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Antimicrobial Cationic Peptides; 0/CD71 antigen; 0/HAMP protein, human; 0/Hamp1 protein, mouse; 0/Hepcidins; 0/Receptors, Transferrin; E1UOL152H7/Iron; EC 3.4.21.-/Subtilisins; EC 3.4.21.-/proprotein convertase PC7; EC 3.4.21.75/Furin
Comments/Corrections
Comment In:
Hepatology. 2013 Nov;58(5):1860-1   [PMID:  23504908 ]
Hepatology. 2013 Nov;58(5):1861-2   [PMID:  23505014 ]

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