title: Cell surface serine protease matriptase-2 suppresses fetuin-A/AHSG-mediated induction of hepcidin.
abstract: Matriptase-2 is a type II transmembrane serine protease controlling the expression of hepcidin, the key regulator of iron homeostasis. By cleaving hemojuvelin, matriptase-2 suppresses bone morphogenetic protein/sons of mothers against decapentaplegic signaling. So far, the only known putative substrates of matriptase-2 are hemojuvelin and matriptase-2 itself. In this study, fetuin-A (α2-Heremans-Schmid glycoprotein) was identified in vitro as a substrate of matriptase-2. The protease-substrate interaction was validated by isolating matriptase-2 via the affinity to fetuin-A. Fetuin-A is a liver-derived plasma protein with multiple functions, which is proteolytically processed to yield a disulfide-linked two-chain form. In co-transfected cells, a matriptase-2-dependent conversion of unprocessed fetuin-A into a two-chain form was detected. Conversely, downregulation of endogenously expressed matriptase-2 stabilized fetuin-A. Arg and Lys residues located within the 40 residue spanning connecting peptide of fetuin-A were identified as cleavage sites for matriptase-2. Analysis of hepcidin expression revealed an inductive effect of fetuin-A, which was abolished by matriptase-2. Fetuin-A deficiency in mice resulted in decreased hepcidin mRNA levels. These findings implicate a role of fetuin-A in iron homeostasis and provide new insights into the mechanism of how matriptase-2 might modulate hepcidin expression.
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
authors.forename: Eva
authors.initials: E
authors.lastname: Maurer
authors.forename: Katharina
authors.initials: K
authors.lastname: Arenz
authors.forename: Anne
authors.initials: A
authors.lastname: Babler
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D000818:Animals; D060748:Fetuins / Q000235:genetics / Q000378:metabolism*; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D012697:Serine Endopeptidases / Q000235:genetics*; D057057:Serine Proteases; D015398:Signal Transduction
chemical_list: D060748:Fetuins; D064451:Hepcidins; D008565:Membrane Proteins; D057057:Serine Proteases; D012697:Serine Endopeptidases; C467801:matriptase 2