Mucus Detachment by Host Metalloprotease Meprin β Requires Shedding of Its Inactive Pro-form, which Is Abrogated by the Pathogenic Protease RgpB.

Rielana Wichert, Anna Ermund, Stefanie Schmidt, Matthias Schweinlin, Miroslaw Ksiazek, Philipp Arnold, Katharina Knittler, Frederike Wilkens, Barbara Potempa, Björn Rabe, Marit Stirnberg, Ralph Lucius, Jörg W Bartsch, Susanna Nikolaus, Maren Falk-Paulsen, Philip Rosenstiel, Marco Metzger, Stefan Rose-John, Jan Potempa, Gunnar C Hansson, Peter J Dempsey, Christoph Becker-Pauly
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Cell reports
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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.