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

Journal article
Authors R. Wichert
Anna Ermund
S. Schmidt
M. Schweinlin
M. Ksiazek
P. Arnold
K. Knittler
F. Wilkens
B. Potempa
B. Rabe
M. Stirnberg
R. Lucius
J. W. Bartsch
S. Nikolaus
M. Falk-Paulsen
P. Rosenstiel
M. Metzger
S. Rose-John
J. Potempa
Gunnar C. Hansson
P. J. Dempsey
C. Becker-Pauly
Published in Cell Reports
Volume 21
Issue 8
Pages 2090-2103
ISSN 2211-1247
Publication year 2017
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 2090-2103
Language en
Links dx.doi.org/10.1016/j.celrep.2017.10...
Keywords aminobenzoic acid hydrolase, inflammatory-bowel-disease, functional cftr, channel, cystic-fibrosis mucus, cell-cell adhesion, porphyromonas-gingivalis, targeted disruption, epithelial-cells, small-intestine, alpha-subunit
Subject categories Cell biology

Abstract

The host metalloprotease meprin beta is required for mucin 2 (MUC2) cleavage, which drives intestinal mucus detachment and prevents bacterial over-growth. To gain access to the cleavage site in MUC2, meprin b must be proteolytically shed from epithelial cells. Hence, regulation of meprin b shedding and activation is important for physiological and pathophysiological conditions. Here, we demonstrate that meprin b 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 beta and is completely inhibited upon its conversion to the active form at the cell surface. This strict regulation of meprin beta activity can be overridden by pathogens, as demonstrated for the bacterial protease Arg-gingipain (RgpB). This secreted cysteine protease potently converts membrane-bound meprin beta into its active form, impairing meprin beta shedding and its function as a mucus-detaching protease.

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