Biological functions and regulation of serglycin-dependent mast cell proteases

摘要: Mast cells (MCs) are immune that release preformed mediators from granules when activated by e.g. bacteria, viruses and allergens. Among the granule components proteoglycans, histamine proteases (chymase, tryptase carboxypeptidase A). The bound to serglycin proteoglycans in granules, some remain attached after expulsion secretory granules. importance of interaction between is exemplified MCs lacking an enzyme essential for heparin biosynthesis, N-deactylase/Nsulfotransferase-2 (NDST-2). Mice with this deficit display impaired storage many MC components, histamine. We could show polycationic compounds inhibited chymase (mMCP-4/rMCP-1) disrupting its heparin. Furthermore, these polycations human (recombinant βI-tryptase) made otherwise resilient susceptible macromolecular inhibitors. Our findings may be therapeutic interest treating pathologies associated enzymes. take part regulation blood pressure angiogenesis, occur through metabolism peptide angiotensin I (AngI). confirmed involvement AngI processing using NDST-2 deficient mice. subsequently elucidated responsible were (mMCP-4) A (CPA), they acted concert on AngI, producing both elevating peptides reducing peptides. implicated connective tissue regulation, a suggested pathway activation matrix degrading enzymes, metalloproteases (MMPs). proMMP-9 dependent MCs, especially mMCP-4, as shown peritoneal cell cultures mice or mMCP-4. Investigation tissues mMCP-4-/- revealed increased deposits extracellular reduced levels MMP-9. Additionally, we proMMP-2 was completely abolished serglycin. showed formation MMP-2 abrogated presence serine protease inhibitors depleted MCs. latter study reveals novel processing, which relevance connection MMP2-associated pathological conditions such cancer.