Mammalian plasma fetuin-B is a selective inhibitor of ovastacin and meprin metalloproteinases.
Konstantin KarmilinCarlo SchmitzMichael KuskeHagen KörschgenMario OlfKatharina MeyerAndré HildebrandMatthias FeltenSven FridrichIrene YiallourosChristoph Becker-PaulyRalf WeiskirchenWilhelm Jahnen-DechentJulia FloehrWalter StöckerPublished in: Scientific reports (2019)
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.
Keyphrases
- extracellular matrix
- endothelial cells
- type diabetes
- single cell
- squamous cell carcinoma
- dna methylation
- genome wide
- stem cells
- young adults
- adipose tissue
- metabolic syndrome
- cell proliferation
- magnetic resonance imaging
- computed tomography
- vascular endothelial growth factor
- copy number
- body composition
- bone marrow
- cell cycle arrest
- genome wide identification
- zika virus
- cell death
- human health
- contrast enhanced
- pi k akt