Mutations in HFE are the most common cause of hereditary hemochromatosis (HH). 
HFE mutations result in reduced expression of hepcidin, a hepatic hormone, which 
negatively regulates iron absorption from the duodenum and iron release from 
macrophages. However, the mechanism by which HFE regulates hepcidin expression 
in hepatocytes is not well understood. It is known that the bone morphogenetic 
protein (BMP) pathway plays a central role in controlling hepcidin expression in 
the liver. Here we show that HFE overexpression increased Smad1/5/8 
phosphorylation and hepcidin expression, whereas inhibition of BMP signaling 
abolished HFE-induced hepcidin expression in Hep3B cells. HFE was found to 
associate with ALK3, inhibiting ALK3 ubiquitination and proteasomal degradation 
and increasing ALK3 protein expression and accumulation on the cell surface. The 
2 HFE mutants associated with HH, HFE C282Y and HFE H63D, regulated ALK3 protein 
ubiquitination and trafficking differently, but both failed to increase ALK3 
cell-surface expression. Deletion of Hfe in mice resulted in a decrease in 
hepatic ALK3 protein expression. Our results provide evidence that HFE induces 
hepcidin expression via the BMP pathway: HFE interacts with ALK3 to stabilize 
ALK3 protein and increase ALK3 expression at the cell surface.