Abstract
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.
Highlights
Vertebrate fetuins are multi-domain plasma-proteins of the cystatin-superfamily
We have shown recently that fertilization in mammals is regulated through the inhibition of the astacin metalloproteinase ovastacin by fetuin-B, a hepatic plasma protein[2,3,4]
Ovastacin is expressed in the oocyte[5] and stored in cortical granules beneath the plasma membrane of the unfertilized egg, which is surrounded by an extracellular matrix termed zona pellucida[6,7,8]
Summary
Vertebrate fetuins are multi-domain plasma-proteins of the cystatin-superfamily. Human fetuin-A is known as AHSG, α2-Heremans-Schmid-glycoprotein. Fetuin-B deficient mice, on the other hand, are female infertile due to zona pellucida ‘hardening’ caused by the metalloproteinase ovastacin in unfertilized oocytes. We have shown recently that fertilization in mammals is regulated through the inhibition of the astacin metalloproteinase ovastacin by fetuin-B, a hepatic plasma protein[2,3,4]. In contrast to single-domain cystatins[16] and kininogens[17], mammalian fetuin-A is incapable of inhibiting cysteine proteinases[15,18], but was identified as an important regulator of mineralized matrix instead[19,20]. Fetuin-B deficient mice are female infertile due to premature zona pellucida ‘hardening’, which is caused by ovastacin activity in unfertilized eggs. In wild type mice the activity of spuriously released ovastacin is inhibited by micromolar concentrations of the plasma protein fetuin-B in the follicular fluid until after fertilization, when complete degranulation of oocytes releases large amounts of ovastacin, which override the fetuin-B inhibition[2,3]
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