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

The host metalloprotease meprin ß 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 ß must be proteolytically shed from epithelial cells. Hence, regulation of meprin ß shedding and activation is important for physiological and pathophysiological conditions. Here, we demonstrate that meprin ß 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 ß and is completely inhibited upon its conversion to the active form at the cell surface. This strict regulation of meprin ß activity can be overridden by pathogens, as demonstrated for the bacterial protease Arg-gingipain (RgpB). This secreted cysteine protease potently converts membrane-bound meprin ß into its active form, impairing meprin ß shedding and its function as a mucus-detaching protease.