Site-specific O-Glycosylation on the MUC2 Mucin Protein Inhibits Cleavage by the Porphyromonas gingivalis Secreted Cysteine Protease (RgpB)
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The colonic epithelial surface is protected by an inner mucus layer that the commensal microflora cannot penetrate. We previously demonstrated that Entamoeba histolytica secretes a protease capable of dissolving this layer that is required for parasite penetration. Here, we asked whether there are bacteria that can secrete similar proteases. We screened bacterial culture supernatants for such activity using recombinant fragments of the MUC2 mucin, the major structural component, and the only gel-forming mucin in the colonic mucus. MUC2 has two central heavily O-glycosylated mucin domains that are protease-resistant and has cysteine-rich N and C termini responsible for polymerization. Culture supernatants of Porphyromonas gingivalis, a bacterium that secretes proteases responsible for periodontitis, cleaved the MUC2 C-terminal region, whereas the N-terminal region was unaffected. The active enzyme was isolated and identified as Arg-gingipain B (RgpB). Two cleavage sites were localized to IR↓TT and NR↓QA. IR↓TT cleavage will disrupt the MUC2 polymers. Because this site has two potential O-glycosylation sites, we tested whether recombinant GalNAc-transferases (GalNAc-Ts) could glycosylate a synthetic peptide covering the IRTT sequence. Only GalNAc-T3 was able to glycosylate the second Thr in IRTT, rendering the sequence resistant to cleavage by RgpB. Furthermore, when GalNAc-T3 was expressed in CHO cells expressing the MUC2 C terminus, the second threonine was glycosylated, and the protein became resistant to RgpB cleavage. These findings suggest that bacteria can produce proteases capable of dissolving the inner protective mucus layer by specific cleavages in the MUC2 mucin and that this cleavage can be modulated by site-specific O-glycosylation.
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Pathogenic bacteria can be expected to have capacities to destroy mucus because they have developed specific mechanisms to circumvent the mucus protective system.
“Such capacities can be expected among pathogenic bacteria as these have developed specific mechanisms to circumvent the mucus protective system 36, 37, 38.”
From The composition of the gut microbiota shapes the colon mucus barrier (2015) · cites this paper as [37]
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- Authors
- van der Post, S., Subramani, D. B., Bäckström, M., Johansson, M. E. V., Vester-Christensen, M. B., Mandel, U., Bennett, E. P., Clausen, H., Dahlén, G., Sroka, A., Potempa, J., & Hansson, G. C.
- Affiliations
- University of Gothenburg (SE)
- University of Copenhagen (DK)
- Jagiellonian University (PL)
- Corresponding author
- Hansson, Gunnar C.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 288
- Issue
- 20
- Pages
- 14636-14646
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3656315
- OpenAlex
- W2038727835
- Cited by
- 89
- References
- 41
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 8 · 2023: 2 · 2022: 2 · 2021: 11 · 2020: 6 · 2019: 2 · 2018: 5 · 2017: 7 · 2016: 5 · 2015: 9 · 2014: 12 · 2013: 4
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Swedish Cancer Foundation (U01AI095473)
- European Commission (POIG.02.01.00-12-064/08)
- National Research Foundation
- Stiftelsen för Strategisk Forskning
- Danmarks Grundforskningsfond
- Fundacja na rzecz Nauki Polskiej (DPS/424-329/10, POIG.02.01.00-12-064/08)
- Knut och Alice Wallenbergs Stiftelse (U01AI095473)
- Vetenskapsrådet (U01AI095473)
- Göteborgs Universitet
- National Institutes of Health
- Sahlgrenska Akademin (U01AI095473)
- National Institute of Allergy and Infectious Diseases (U01AI095473)
- National Institute of Dental and Craniofacial Research (R01DE009761, DE09761)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Keywords
- MUC2, O-glycosylation, Porphyromonas gingivalis, RgpB, cysteine protease, mucus layer, colonic epithelium, GalNAc-T3, GalNAc transferase, protease resistance, bacterial proteases, periodontitis
- MeSH terms
- Gingipain Cysteine Endopeptidases, Amino Acid Sequence, Animals, Chromatography, Colitis, Colon, Cysteine Endopeptidases, Epithelium, Glycosylation, Cricetinae, Humans, Molecular Sequence Data, Mass Spectrometry, CHO Cells, Porphyromonas gingivalis, Adhesins, Bacterial, Mucin-2
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