Mammalian plasma fetuin-B is a selective inhibitor of ovastacin and meprin metalloproteinases

• Published in: Scientific reports 2019-01, Vol.9 (1), p.546-546, Article 546
• Main Authors: Karmilin, Konstantin, Schmitz, Carlo, Kuske, Michael, Körschgen, Hagen, Olf, Mario, Meyer, Katharina, Hildebrand, André, Felten, Matthias, Fridrich, Sven, Yiallouros, Irene, Becker-Pauly, Christoph, Weiskirchen, Ralf, Jahnen-Dechent, Willi, Floehr, Julia, Stöcker, Walter
• Format: Article
• Language: English
• Subjects: 631/136/142; 631/443/494/2732/1577; 631/45/468; 631/80/474; 64/116; 64/60; 692/308/2778; 82; 82/1; 82/16; 82/29; 82/58; 82/80; 82/81; 82/83; alpha-2-HS-Glycoprotein - metabolism; Alzheimer's disease; Angiogenesis; Animals; Astacin; Astacoidea; Bone matrix; Cattle; Cystatins; Cytokines; Enzymes; Extracellular matrix; Fertility; Fertilization - physiology; Fetuin-B - metabolism; Fibrinolysin - metabolism; Fibrosis; Glycoproteins; Glycosylation; Humanities and Social Sciences; Humans; Insect cells; Mammals; Mammals - blood; Matrix Metalloproteinase 9 - metabolism; Metalloendopeptidases - metabolism; Metalloproteases - antagonists & inhibitors; Metalloproteases - metabolism; Metalloproteinase; Mice; Mineralization; multidisciplinary; Neurodegenerative diseases; Oocytes; Peptides; Physiology; Plasma; Plasma - metabolism; Proteinase; Proteinase inhibitors; Proteins; Proteolysis; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Sperm; Zona pellucida
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-37024-5

Vertebrate fetuins are multi-domain plasma-proteins of the cystatin-superfamily. Human fetuin-A is also known as AHSG, α 2 -Heremans-Schmid-glycoprotein. Gene-knockout in mice identified fetuin-A as essential for calcified-matrix-metabolism and bone-mineralization. Fetuin-B deficient mice, on the other hand, are female infertile due to zona pellucida ‘hardening’ caused by the metalloproteinase ovastacin in unfertilized oocytes. In wildtype mice fetuin-B inhibits the activity of ovastacin thus maintaining oocytes fertilizable. Here we asked, if fetuins affect further proteases as might be expected from their evolutionary relation to single-domain-cystatins, known as proteinase-inhibitors. We show that fetuin-A is not an inhibitor of any tested protease. In stark contrast, the closely related fetuin-B selectively inhibits astacin-metalloproteinases such as meprins and ovastacin, but not astacins of the tolloid-subfamily, nor any other proteinase. The analysis of fetuin-B expressed in various mammalian cell types, insect cells, and truncated fish-fetuin expressed in bacteria, showed that the cystatin-like domains alone are necessary and sufficient for inhibition. This report highlights fetuin-B as a specific antagonist of ovastacin and meprin-metalloproteinases. Control of ovastacin was shown to be indispensable for female fertility. Meprin inhibition, on the other hand, renders fetuin-B a potential key-player in proteolytic networks controlling angiogenesis, immune-defense, extracellular-matrix-assembly and general cell-signaling, with implications for inflammation, fibrosis, neurodegenerative disorders and cancer.