title: Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus.
abstract: The mucus that covers and protects the epithelium of the intestine is built around its major structural component, the gel-forming MUC2 mucin. The gel-forming mucins have traditionally been assumed to be secreted as nonattached. The colon has a two-layered mucus system where the inner mucus is attached to the epithelium, whereas the small intestine normally has a nonattached mucus. However, the mucus of the small intestine of meprin β-deficient mice was now found to be attached. Meprin β is an endogenous zinc-dependent metalloprotease now shown to cleave the N-terminal region of the MUC2 mucin at two specific sites. When recombinant meprin β was added to the attached mucus of meprin β-deficient mice, the mucus was detached from the epithelium. Similar to meprin β-deficient mice, germ-free mice have attached mucus as they did not shed the membrane-anchored meprin β into the luminal mucus. The ileal mucus of cystic fibrosis (CF) mice with a nonfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channel was recently shown to be attached to the epithelium. Addition of recombinant meprin β to CF mucus did not release the mucus, but further addition of bicarbonate rendered the CF mucus normal, suggesting that MUC2 unfolding exposed the meprin β cleavage sites. Mucus is thus secreted attached to the goblet cells and requires an enzyme, meprin β in the small intestine, to be detached and released into the intestinal lumen. This process regulates mucus properties, can be triggered by bacterial contact, and is nonfunctional in CF due to poor mucin unfolding.
authors.affiliation: Departments of Medical Biochemistry and.
authors.forename: André
authors.initials: A
authors.lastname: Schütte
authors.affiliation: Departments of Medical Biochemistry and.
authors.forename: Anna
authors.initials: A
authors.lastname: Ermund
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, Christian Albrechts University, 24118 Kiel, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.affiliation: Departments of Medical Biochemistry and.
authors.forename: Malin E V
authors.initials: ME
authors.lastname: Johansson
authors.affiliation: Departments of Medical Biochemistry and.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Rodriguez-Pineiro
authors.affiliation: Molecular and Clinical Medicine, University of Gothenburg, 40530 Gothenburg, Sweden;
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: FACSlab, Institute of Pathology, and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lottaz
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, Hershey, PA 17033.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Bond
authors.affiliation: Departments of Medical Biochemistry and gunnar.hansson@medkem.gu.se.
authors.forename: Gunnar C
authors.initials: GC
authors.lastname: Hansson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005856:Germ-Free Life / Q000502:physiology; D007421:Intestine, Small / Q000378:metabolism* / Q000382:microbiology; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D055262:Mucin-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009093:Mucus / Q000378:metabolism*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: C524626:Muc2 protein, mouse; D055262:Mucin-2; D011994:Recombinant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D008666:Metalloendopeptidases; C053833:meprin A
keywords: gastrointestinal tract; protease; von Willebrand factor
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