Format

Send to

Choose Destination
Cell Rep. 2017 Nov 21;21(8):2090-2103. doi: 10.1016/j.celrep.2017.10.087.

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

Author information

1
Institute of Biochemistry, University of Kiel, Kiel, Germany.
2
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden.
3
Department of Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, Würzburg, Germany.
4
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
5
Anatomical Institute, University of Kiel, Kiel, Germany.
6
Pharmaceutical Institute, University of Bonn, Bonn, Germany.
7
Department of Neurosurgery, Philipps University Marburg, Marburg, Germany.
8
I. Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany.
9
Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany.
10
Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Translational Center "Regenerative Therapies for Oncology and Musculoskeletal Diseases" - Würzburg Branch, Würzburg, Germany.
11
Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, USA.
12
Department of Pediatrics, University of Colorado Medical School, Aurora, CO 80045, USA.
13
Institute of Biochemistry, University of Kiel, Kiel, Germany. Electronic address: cbeckerpauly@biochem.uni-kiel.de.

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.

KEYWORDS:

ectodomain shedding; host-microbiome interaction; intestinal mucus barrier; metalloprotease; mucus

PMID:
29166602
DOI:
10.1016/j.celrep.2017.10.087
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center