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Blood, 15 January 2008, Vol. 111, No. 2, pp. 924-931.
Prepublished online as a Blood First Edition Paper on October 15, 2007; DOI 10.1182/blood-2007-07-100677.
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Submitted July 10, 2007
Accepted October 10, 2007
Furin mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis
Laura Silvestri, Alessia Pagani, and Clara Camaschella*
Vita-Salute San Raffaele University - IRCCS, San Raffaele, Milan, Italy
* Corresponding author; email: camaschella.clara{at}hsr.it.
The liver peptide hepcidin regulates the 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 (m)-HJV acts as a coreceptor for bone-morphogenetic-proteins (BMP), whereas soluble (s)-HJV may downregulate 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 two 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 upregulated by iron deficiency and hypoxia in association with the stabilization of HIF-1 . Increased s-HJV in response to HIF-1 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.
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