Mammalian plasma fetuin-B is a selective inhibitor of ovastacin and meprin metalloproteinases
| Autor: | Sven Fridrich, Walter Stöcker, Matthias Felten, Ralf Weiskirchen, Carlo Schmitz, Julia Floehr, Irene Yiallouros, Katharina Meyer, Hagen Körschgen, Willi Jahnen-Dechent, Michael Kuske, André Hildebrand, Mario Olf, Konstantin Karmilin, Christoph Becker-Pauly |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Proteases Glycosylation alpha-2-HS-Glycoprotein medicine.medical_treatment Proteolysis lcsh:Medicine Astacoidea Matrix metalloproteinase Article 03 medical and health sciences Mice Plasma 0302 clinical medicine medicine Animals Humans Fibrinolysin Zona pellucida lcsh:Science Mammals Metalloproteinase Multidisciplinary Protease medicine.diagnostic_test Chemistry lcsh:R Wild type Metalloendopeptidases Fetuin Fetuin-B Recombinant Proteins Cell biology 030104 developmental biology medicine.anatomical_structure Matrix Metalloproteinase 9 Fertilization Metalloproteases Cattle lcsh:Q 030217 neurology & neurosurgery |
| Zdroj: | Scientific reports 9, 546 (2019). doi:10.1038/s41598-018-37024-5 Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) Scientific Reports |
| DOI: | 10.1038/s41598-018-37024-5 |
| Popis: | Vertebrate fetuins are multi-domain plasma-proteins of the cystatin-superfamily. Human fetuin-A is also known as AHSG, α2-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. |
| Databáze: | OpenAIRE |
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