title: HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression.
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.
authors.affiliation: Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
authors.forename: Xing-Gang
authors.initials: XG
authors.lastname: Wu
authors.affiliation: Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nutrition, Center for Nutrition and Health, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China;
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
authors.forename: Wai-Hang
authors.initials: WH
authors.lastname: Cheng
authors.affiliation: Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
authors.forename: Wenjing
authors.initials: W
authors.lastname: Liu
authors.affiliation: Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
authors.forename: Yueshui
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital.
authors.forename: Claire
authors.initials: C
authors.lastname: Mayeur
authors.affiliation: Department of Pathology, Boston Children's Hospital, and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Schmidt
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.affiliation: Department of Nutrition, Center for Nutrition and Health, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China;
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
authors.affiliation: Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; School of Biomedical Sciences Core Laboratory, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Xia
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000502:physiology*; D000071020:Hemochromatosis Protein; D056945:Hep G2 Cells; D064451:Hepcidins / Q000096:biosynthesis* / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051785:Smad Proteins / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
chemical_list: C578702:HAMP protein, human; C103673:HFE protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D051785:Smad Proteins; C498211:BMPR1A protein, human; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D053505:Matrix Metalloproteinases, Secreted; D046988:Proteasome Endopeptidase Complex