The Densely O-Glycosylated MUC2 Mucin Protects the Intestine and Provides Food for the Commensal Bacteria

Abstract

All mucins are highly O-glycosylated by variable glycans depending on species, histoblood group and organ. This makes the intestinal main mucin MUC2 non-degradable by the host digestive system but well by both commensal and pathogenic bacteria. The MUC2 glycans are important for selection of the commensal bacteria and act as a nutritional source for the bacteria; this also helps the host to recover some of the energy spent on constantly renewing the protective mucus layer. Glycosylation is the most diverse and common posttranslational modification of cell surfaces and secreted proteins. N-Glycosylation is most well studied and predictable, whereas O-glycosylation is more diverse and less well understood. O-Glycosylation is also often called mucin-type glycosylation as it is typical for mucins that often have more than 80% of the mass as O-glycans. This review will discuss the mucin-type O-glycosylation and especially the O-glycosylation of human and mice intestinal mucin MUC2 in relation to bacteria and disease.

Keywords: colon; glycosylation; glycosyltransferase; mucus; small intestine.

Fig. 1. The MUC2 mucin structure with examples of O-glycans attached to the PTS sequences

The MUC2 mucin forms large net-like sheets by N-terminal trimerization and C-terminal dimerization.

Fig. 2. Conventionalization of germ-free mice alters glycosyltransferase levels and glycans

Major glycans found on Muc2 in mouse colon and arrows showing increased/decreased levels upon conventionalization of germ-free (GF) mice. The relative molecular abundances of the glycosyltransferases in conventionally raised (Conv-R) and germ-free (GF) mice. Results from Holmen et al. [41] and Johansson et al. [45]. C1galt1c1 is the cosmic chaperone [76].

Fig. 3. Protection of human MUC2 susceptible cleavage sites by specific peptidyl-GalNAc transferase 3

Schematic figure of MUC2 showing the part where proteolytic cleavage might dissolve the MUC2 polymer network. Cleavage sites for the Entamoeba histolytica EhCP and Porphyrinomonas aerogenosa RgpB proteases dissolving the human MUC2 polymer if not glycosylated by GALNT3, the most abundant peptidyl-GalNAc transferase in human colon. Results from Lidell et al. [62] and van der Post et al. [63,64].

Fig. 4. Reversible alterations of the MUC2 O-glycans upon active inflamed ulcerative colitis (UC)

Major MUC2 O-glycans in human sigmoid colon of control individuals and patients with inactive UC disease. Arrows show alterations in patients with active UC. The relative amounts of the glycosyltransferases used for the biosynthesis of the glycans in human control individuals are shown as dots. Results from Holmen-Larsson et al. [74] and van der Post et al. [64].