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Mucus detachment by host metalloprotease meprin β requires shedding of its inactive pro-form, which is abrogated by the pathogenic protease RgpB

 
: 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, Jörg W.; Nikolaus, Susanna; Falk-Paulsen, Maren; Rosenstiel, Philip; Metzger, Marco; Rose-John, Stefan; Potempa, Jan; Hansson, Gunnar C.; Dempsey, Peter J.; Becker-Pauly, Christoph

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Fulltext (PDF; )

Cell reports 21 (2017), No.8, pp.2090-2103
ISSN: 2211-1247
English
Journal Article, Electronic Publication
Fraunhofer ISC ()
Fraunhofer IGB ()
Schleim; Protein

Abstract
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.

: http://publica.fraunhofer.de/documents/N-481341.html