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
Affiliations
Rielana Wichert
Institute of Biochemistry, University of Kiel, Kiel, Germany
Anna Ermund
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Stefanie Schmidt
Institute of Biochemistry, University of Kiel, Kiel, Germany
Matthias Schweinlin
Department of Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, Würzburg, Germany
Miroslaw Ksiazek
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland
Philipp Arnold
Anatomical Institute, University of Kiel, Kiel, Germany
Katharina Knittler
Institute of Biochemistry, University of Kiel, Kiel, Germany
Frederike Wilkens
Institute of Biochemistry, University of Kiel, Kiel, Germany
Barbara Potempa
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland
Björn Rabe
Institute of Biochemistry, University of Kiel, Kiel, Germany
Marit Stirnberg
Pharmaceutical Institute, University of Bonn, Bonn, Germany
Ralph Lucius
Anatomical Institute, University of Kiel, Kiel, Germany
Jörg W. Bartsch
Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
Susanna Nikolaus
I. Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
Maren Falk-Paulsen
Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany
Philip Rosenstiel
Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany
Marco Metzger
Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Translational Center “Regenerative Therapies for Oncology and Musculoskeletal Diseases” – Würzburg Branch, Würzburg, Germany
Stefan Rose-John
Institute of Biochemistry, University of Kiel, Kiel, Germany
Jan Potempa
Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, USA
Gunnar C. Hansson
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
Peter J. Dempsey
Department of Pediatrics, University of Colorado Medical School, Aurora, CO 80045, USA
Christoph Becker-Pauly
Institute of Biochemistry, University of Kiel, Kiel, Germany
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.
