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HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression
- Source :
- Blood. 124:1335-1343
- Publication Year :
- 2014
- Publisher :
- American Society of Hematology, 2014.
-
Abstract
- 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.
- Subjects :
- Proteasome Endopeptidase Complex
congenital, hereditary, and neonatal diseases and abnormalities
medicine.medical_specialty
Immunology
Mutation, Missense
Smad Proteins
medicine.disease_cause
Bone morphogenetic protein
digestive system
Biochemistry
Mice
Hepcidins
Inside BLOOD Commentary
Hepcidin
Internal medicine
Chlorocebus aethiops
Matrix Metalloproteinases, Secreted
medicine
Animals
Humans
Bone morphogenetic protein receptor
Hemochromatosis Protein
Bone Morphogenetic Protein Receptors, Type I
Mice, Knockout
Regulation of gene expression
Mutation
biology
Chemistry
Histocompatibility Antigens Class I
digestive, oral, and skin physiology
Ubiquitination
Membrane Proteins
nutritional and metabolic diseases
Hep G2 Cells
Cell Biology
Hematology
Protein ubiquitination
Cell biology
Endocrinology
Amino Acid Substitution
Gene Expression Regulation
Hereditary hemochromatosis
COS Cells
Proteolysis
biology.protein
Phosphorylation
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 124
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....2acbf6cba1e73f538f715c0e1b38a5a6