Institute of Biochemistry, University of Kiel, Kiel, Germany.
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden.
Cell Rep. 2017 Nov 21;21(8):2090-2103. doi: 10.1016/j.celrep.2017.10.087.
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. Employing ex vivo small 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.
宿主金属蛋白酶 meprin β 是黏蛋白 2（MUC2）裂解所必需的，它驱动肠道黏液脱落，防止细菌过度生长。为了接近 MUC2 中的裂解位点，meprins β 必须从上皮细胞中进行蛋白水解脱落。因此，meprins β 脱落和激活的调节对于生理和病理生理条件非常重要。在这里，我们证明 meprin β 的激活和脱落是相互排斥的事件。通过使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 pro 形式的 meprin β，并且在其在细胞表面转化为活性形式时完全被抑制。这种严格的 meprin β 活性调节可以被病原体超越，正如细菌蛋白酶 Arg-gingipain（RgpB）所证明的那样。这种分泌的半胱氨酸蛋白酶可有效地将膜结合的 meprin β 转化为其活性形式，从而损害 meprin β 的脱落及其作为黏液脱落蛋白酶的功能。
