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

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


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.

MeSH terms

  • Adhesins, Bacterial / metabolism*
  • Amino Acid Sequence / genetics
  • Animals
  • Cell Membrane / metabolism
  • Cysteine Endopeptidases / metabolism*
  • Epithelial Cells / metabolism
  • Female
  • Gingipain Cysteine Endopeptidases
  • HEK293 Cells
  • Humans
  • Male
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Metalloproteases / metabolism*
  • Mice, Transgenic
  • Mucin-2 / genetics
  • Mucin-2 / metabolism


  • Adhesins, Bacterial
  • Gingipain Cysteine Endopeptidases
  • MUC2 protein, human
  • Mucin-2
  • Metalloproteases
  • Cysteine Endopeptidases
  • Metalloendopeptidases
  • meprin B