Mucus Detachment by Host Metalloprotease Meprin β Requires Shedding of Its Inactive Pro-form, which Is Abrogated by the Pathogenic Protease RgpB.
Mucus Detachment by Host Metalloprotease Meprin β Requires Shedding of Its Inactive Pro-form, which Is Abrogated by the Pathogenic Protease RgpB.
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宿主金属蛋白酶 Meprin β 的粘液分离需要脱落其非活性前体形式，而该前体形式可被致病性蛋白酶 RgpB 消除。
DOI：
10.1016/j.celrep.2017.10.087
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发表时间：
2017
期刊：
影响因子：
8.8
通讯作者：
Falk-
中科院分区：
文献类型：
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作者：
Wichert,Rielana;Ermund,Anna;Schmidt,Stefanie;Schweinlin,Matthias;Ksiazek,Miroslaw;Arnold,Philipp;Knittler,Katharina;Wilkens,Frederike;Potempa,Barbara;Rabe,Björn;Stirnberg,Marit;Lucius,Ralph;Bartsch,JörgW;Nikolaus,Susanna;Falk-
宿主金属蛋白酶meprin β是粘蛋白2（MUC 2）切割所必需的，其驱动肠粘液脱离并防止细菌过度生长。为了进入MUC 2中的切割位点，meprin β必须通过蛋白水解从上皮细胞脱落。因此，调节meprin β脱落和活化对于生理和病理生理条件是重要的。在这里，我们证明了meprin β激活和脱落是相互排斥的事件。利用离体小肠类器官和细胞培养实验，我们发现ADAM介导的脱落仅限于无活性的meprin β前体形式，并且在其转化为细胞表面的活性形式时被完全抑制。如细菌蛋白酶Arg-gingipain（RgpB）所证明的，这种对meprin β活性的严格调节可以被病原体所推翻。这种分泌的半胱氨酸蛋白酶有效地将膜结合的美普林β转化为其活性形式，从而损害美普林β脱落及其作为粘液分离蛋白酶的功能。
The host metalloprotease meprin β is required for mucin 2 (MUC2) cleavage, which drives intestinal mucus detachment and prevents bacterial overgrowth. To gain access to the cleavage site in MUC2, meprin β must be proteolytically shed from epithelial cells. Hence, regulation of meprin β shedding and activation is important for physiological and pathophysiological conditions. Here, we demonstrate that meprin β activation and shedding are mutually exclusive events. Employingex vivosmall intestinal organoid and cell culture experiments, we found that ADAM-mediated shedding is restricted to the inactive pro-form of meprin β and is completely inhibited upon its conversion to the active form at the cell surface. This strict regulation of meprin β activity can be overridden by pathogens, as demonstrated for the bacterial protease Arg-gingipain (RgpB). This secreted cysteine protease potently converts membrane-bound meprin β into its active form, impairing meprin β shedding and its function as a mucus-detaching protease.