Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis.
The liver peptide hepcidin regulates iron absorption and recycling. Hemojuvelin (HJV) has a key role in hepcidin regulation, and its inactivation causes severe iron overload both in humans and in mice. Membrane HJV (m-HJV) acts as a coreceptor for bone morphogenetic proteins (BMPs), whereas soluble HJV (s-HJV) may down-regulate hepcidin in a competitive way interfering with BMP signaling. s-HJV is decreased by iron in vitro and increased by iron deficiency in vivo. However, the mechanisms regulating the 2 HJV isoforms remain unclear. Here we show that s-HJV originates from a furin cleavage at position 332-335. s-HJV is reduced in the cleavage mutant R335Q as well as in cells treated with a furin inhibitor, and increased in cells overexpressing exogenous furin, but not in cells overexpressing an inactive furin variant. Furin is up-regulated by iron deficiency and hypoxia in association with the stabilization of HIF-1alpha. Increased s-HJV in response to HIF-1alpha occurs during differentiation of murine muscle cells expressing endogenous Hjv. Our data are relevant to the mechanisms that relate iron metabolism to the hypoxic response. The release of s-HJV might be a tissue-specific mechanism, signaling the local iron requests of hypoxic skeletal muscles independently of the oxygen status of the liver.
Silvestri
Laura
L
Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele, Milan, Italy.
Pagani
Alessia
A
Camaschella
Clara
C
D019943:Amino Acid Substitution; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D058851:GPI-Linked Proteins; D006367:HeLa Cells; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D019190:Iron Overload / Q000235:genetics / Q000382:microbiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D020125:Mutation, Missense; D009928:Organ Specificity / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C497442:HIF1A protein, human; C481006:HJV protein, human; C504414:HJV protein, mouse; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D020033:Protein Isoforms; D007501:Iron; C468731:FURIN protein, human; D045683:Furin; D010100:Oxygen