Journal
CELL REPORTS
Volume 21, Issue 8, Pages 2090-2103Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.10.087
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [BE4086/5-1, STI 660/1-1, SFB 877]
- DFG Excellence Cluster [306]
- NIH [U01AI095473, R01DE009761, R21DE026280]
- National Science Center (NCN, Krakow, Poland) [2012/04/A/NZ1/00051]
- European Commission (TRIGGER'') [FP7-HEALTH-F3-2012-306029]
- ERC [694181]
- Polish Ministry of Science and Higher Education [MNiSW 2975/7.PR/13/2014/2]
- MNiSW
- European Research Council (ERC) [694181] Funding Source: European Research Council (ERC)
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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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