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Cell surface serine protease matriptase-2 suppresses fetuin-A/AHSG-mediated induction of hepcidin

  • Marit Stirnberg EMAIL logo , Eva Maurer , Katharina Arenz , Anne Babler , Willi Jahnen-Dechent and Michael Gütschow
Published/Copyright: September 2, 2014
Biological Chemistry
From the journal Biological Chemistry Volume 396 Issue 1

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.

Keywords: α2-Heremans-Schmid glycoprotein; iron homeostasis; type II transmembrane serine protease
Corresponding author: Marit Stirnberg, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany, e-mail:

Acknowledgments

M.S. is supported by Deutsche Forschungsgemeinschaft Grant STI 660/1-1. E.M. was supported by a fellowship from Bayer HealthCare Pharmaceuticals, Wuppertal, Germany. We thank Dr Paolo Arosio (Università degli Studi di Brescia, Italy) for providing the HJV antibody.

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Supplemental Material

The online version of this article (DOI: 10.1515/hsz-2014-0120) offers supplementary material, available to authorized users.

Received: 2014-2-7
Accepted: 2014-5-19
Published Online: 2014-9-2
Published in Print: 2015-1-1

©2014 by De Gruyter

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https://doi.org/10.1515/hsz-2014-0120
Keywords for this article
α2-Heremans-Schmid glycoprotein; iron homeostasis; type II transmembrane serine protease

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Cholesterol lowering: role in cancer prevention and treatment
  4. The role of the Mpv17 protein mutations of which cause mitochondrial DNA depletion syndrome (MDDS): lessons from homologs in different species
  5. Research Articles/Short Communications
  6. Genes and Nucleic Acids
  7. Identification of a novel PHEX mutation in a Chinese family with X-linked hypophosphatemic rickets using exome sequencing
  8. Protein Structure and Function
  9. Complement activation by salivary agglutinin is secretor status dependent
  10. Synthesis, biological evaluation, and docking studies of PAR2-AP-derived pseudopeptides as inhibitors of kallikrein 5 and 6
  11. Membranes, Lipids, Glycobiology
  12. Recombinant HDL (Milano) protects endotoxin-challenged rats from multiple organ injury and dysfunction
  13. Cell Biology and Signaling
  14. miR-126 regulates platelet-derived growth factor receptor-α expression and migration of primary human osteoblasts
  15. Legumain expression, activity and secretion are increased during monocyte-to-macrophage differentiation and inhibited by atorvastatin
  16. Proteolysis
  17. Cell surface serine protease matriptase-2 suppresses fetuin-A/AHSG-mediated induction of hepcidin
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