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;).