Mannan-binding protein blocks the activation of metalloproteases meprin α and β
Mannan-binding protein blocks the activation of metalloproteases meprin α and β
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DOI：
10.4049/jimmunol.175.5.3177
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发表时间：
2005-09-01
影响因子：
4.4
通讯作者：
Kawasaki, T
中科院分区：
文献类型：
--
作者：
Hirano, M;Ma, BY;Kawasaki, T
甘露聚糖结合蛋白（MBP）是一种C型血清凝集素，已知是参与先天免疫的宿主防御因子，并识别甘露糖、岩藻糖和N-乙酰葡糖胺残基。虽然已经报道了一些外源性MBP配体，但对其内源性配体知之甚少。在本研究中，我们发现，内源性MBP配体的高表达的刷状缘上皮细胞的肾近端小管，和meprin α和β（meprins），作为新的内源性MBP配体，已被确定通过亲和层析和质谱。Meprins是膜结合和分泌的锌金属蛋白酶，广泛糖基化并在肾和小肠上皮细胞、白细胞和某些癌细胞中高度表达。Meprins能够切割生长因子、细胞外基质蛋白和生物活性肽。去糖基化实验表明，在meprins上的MBP配体是高甘露糖或复合型N-聚糖。MBP与meprins的相互作用导致meprins的蛋白水解活性和基质降解能力显著降低。我们的研究结果表明，核心N-连接的寡糖对meprins与最佳的酶活性和MBP是一个重要的调节器，通过N-聚糖结合的调制本地meprin蛋白水解活性。由于已知meprins是肾脏和肠道中的一些主要基质降解金属蛋白酶，因此作为meprins的天然有效抑制剂的MBP可能作为潜在的治疗靶点，通过促进癌细胞的迁移、内渗和转移而促进肿瘤进展，并促进急性肾衰竭和炎性肠病。
Mannan-binding protein (MBP) is a C-type serum lectin that is known to be a host defense factor involved in innate immunity, and recognizes mannose, fucose, and N-acetylglucosamine residues. Although some exogenous MBP ligands have been reported, little is known about its endogenous ligands. In the present study, we found that endogenous MBP ligands are highly expressed in the brush border epithelial cells of kidney-proximal tubules by immunohistochemistry, and both meprin alpha and beta (meprins), as novel endogenous MBP ligands, have been identified through affinity chromatography and mass spectrometry. Meprins are membrane-bound and secreted zinc metalloproteases extensively glycosylated and highly expressed in kidney and small intestinal epithelial cells, leukocytes, and certain cancer cells. Meprins are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. Deglycosylation experiments indicated that the MBP ligands on meprins are high mannose- or complex-type N-glycans. The interaction of MBP with meprins resulted in significant decreases in the proteolytic activity and matrix-degrading ability of meprins. Our results suggest that core N-linked oligosaccharides on meprins are associated with the optimal enzymatic activity and that MBP is an important regulator for modulation of the localized meprin proteolytic activity via N-glycan binding. Because meprins are known to be some of the major matrix-degrading metalloproteases in the kidney and intestine, MBP, which functions as a natural and effective inhibitor of meprins, may contribute, as a potential therapeutic target, to tumor progression by facilitating the migration, intravasation, and metastasis of carcinoma cells, and to acute renal failure and inflammatory bowel diseases.