6533b862fe1ef96bd12c6522

RESEARCH PRODUCT

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

Sven FridrichWalter StöckerMatthias FeltenRalf WeiskirchenCarlo SchmitzJulia FloehrIrene YiallourosKatharina MeyerHagen KörschgenWilli Jahnen-dechentMichael KuskeAndré HildebrandMario OlfKonstantin KarmilinChristoph Becker-pauly

subject

0301 basic medicineProteasesGlycosylationalpha-2-HS-Glycoproteinmedicine.medical_treatmentProteolysislcsh:MedicineAstacoideaMatrix metalloproteinaseArticle03 medical and health sciencesMicePlasma0302 clinical medicinemedicineAnimalsHumansFibrinolysinZona pellucidalcsh:ScienceMammalsMetalloproteinaseMultidisciplinaryProteasemedicine.diagnostic_testChemistrylcsh:RWild typeMetalloendopeptidasesFetuinFetuin-BRecombinant ProteinsCell biology030104 developmental biologymedicine.anatomical_structureMatrix Metalloproteinase 9FertilizationProteolysisMetalloproteasesCattlelcsh:Q030217 neurology & neurosurgery

description

AbstractVertebrate 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.

10.1038/s41598-018-37024-5https://publications.rwth-aachen.de/record/761085