Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewMucins: A biologically relevant glycan barrier in mucosal protection
Introduction
Mucosal surfaces throughout the body require protection against the variety of aggressive agents they encounter during the fulfilment of their normal function [1], [2]. The mucins are an integral component in the mucus gel blanket found at these locations [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. The variety of functions include gaseous exchange especially in the respiratory tree, nutrient and cofactor adsorption in the gut, transparency at the ocular surface and general roles such as lubrication, and chemical sensing. In addition, the mucosal surfaces have a close and integrated relationship to both innate and adaptive immune systems and are linked to the systemic circulation. These processes are closely related with the development of diseases at mucosal surfaces. [3], [16], [17], [18], [19], [20], [21], [22]. Thus, mucosal epithelia throughout the body can be considered to be vital and dynamic entities in regular function and interaction of the body with both internal and external environments encountered on a daily basis. The airways, gastrointestinal and genitourinary tracts, the ocular surface, nasal cavity, mouth and throat are primary sites, while the cornea, cervix and upper gastrointestinal mucosa are accessed via the primary sites. As a result the mucus generated varies between each mucosal surface and requires careful investigation and characterisation in order to allow relevant study of normal and pathological functionality. Furthermore, the general mucoadhesion properties encountered at the mucosal surfaces provide a focus for drug delivery [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]. Recently attention has been drawn to the short term changes associated with collected mucus samples and caution is required when extrapolating results to physiological or biological situations [40].
The complexity of the protective mucosal barrier is expected due to the variety of roles and functions carried out at these locations in a continuous and dynamic manner. The normal turnover of the barrier is essential if an ongoing and viable defence is to be maintained [41], [42], [43]. This is reflected in the balance between biosynthesis, secretion and degradation. The enzymatic pathways responsible for biosynthesis and degradation are well known and in addition a range of proteins interacting with the glycan units of these glycoconjugates can be found on the CaZY website [44], illustrating the wide array of manipulations available to achieve normal, dynamic function and protection. The presence of these enzymes and proteins across the evolutionary spectrum underlines the fundamental significance of glycans in biology and stresses the need to better understand the intricacies of this system.
The main aim of this review is to present the molecular properties and functional attributes of the mucins in humans from the viewpoint of their glycobiology. This family of O-glycosylated macromolecules represent a glycoarray located on cell surfaces, the extracellular matrix and in the external environment. They have been implicated in many disease processes and a number of examples have been chosen to illustrate this point. We are now starting to appreciate the relevance of such glycoarrays at the biological level and recent advances have emphasised their importance [13], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54].
Section snippets
Mucus gels, mucins and the protective mucosal barrier
The mucus layer found at mucosal surfaces throughout the body depends on the mucins or mucus glycoproteins to generate the biophysical and biochemical properties required for optimal mucosal protection. The viscoelastic, rheological and chemical properties of this group of molecules is adapted to physiological requirements dictated by the site of expression in the body. Mucins have evolved [55], leading to the family of over 20 MUC genes, which are shown in Table 1 and are found on a tissue
Glycosylation of mucins and glycobiology
The mucins are glycoproteins rich in O-linked, “mucin type” glycans. The characteristic mucin domains rich in proline/threonine/serine motifs (PTS domains) are the primary site of this glycosylation. The serine and threonine residues are the linkage amino acids, in each case through N-acetyl-d-galactosamine. The peptide attachment site for the O-glycans is recognised by the family of UDP-N-acetylgalactosamine: polypeptide N-acetylgalactosaminyltransferases (ppGaNTases) [154], [155] and is in
Interaction of the mucin glycoarray with the microflora
The mucosal mucin glycoarray at all sites throughout the body interacts with the native microflora and is a major emphasis of attention. Improvements in genomic screening and mapping technology have led to the documentation of numerous microbiomes which have played a significant part in current understanding of host microflora relationships [118], [119], [120], [121], [123], [131], [180], [181]. The formation of a mucosal gel layer has been detailed at a number of mucosal surfaces [2], [6], [8]
The role of mucins and glycogenes in cancer and mucosal diseases
The impact of mucins and their glycoarrays in disease is a very large topic and has been reviewed widely to include both secreted and membrane-associated forms [165], [169], [238], [239], [240], [241], [242], [243], [244], [245]. Changes in glycosylation will influence all glycoconjugates, including the mucins. In this section a few well defined examples have been chosen to illustrate this phenomenon. In some cases the major focus has been non-mucin glycoconjugates, but the identified
Concluding remarks
This review draws attention to the variety of mucin genes and their glycosylation that are known to play roles at mucosal surfaces throughout the body. The scope and adaptation of this family of molecules to their function is enormous and attracts constant reconsideration in the light of the plethora of biological events where they are implicated. The abundance of mucin literature available has meant that some aspects have not been covered in full, however the focus presented here will give
Acknowledgements and funding
This review is dedicated to two giants in the field of mucins and gastrointestinal pathology who have recently died. John Sheehan, the embodiment of knowledge, enthusiasm and originality for all mucineers. Bryan Warren, whose expertise, awareness and depth of understanding was a constant delight for those of us trying to grapple with the boundaries of histopathology.
Support for the work carried out by Anthony Corfield in Mucin Research Group in Bristol was received from the Wellcome Trust, BBSRC
References (351)
- et al.
Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases
Biochim. Biophys. Acta
(2006) - et al.
Architecture of the large membrane-bound mucins
Gene
(2008) Role of mucus layers in gut infection and inflammation
Curr. Opin. Microbiol.
(2012)- et al.
Mucins in the mucosal barrier to infection
Nat. Rev. Immunol.
(2008) - et al.
Glycans as cancer biomarkers
Biochim. Biophys. Acta
(2012) - et al.
Development and in vitro evaluation of a mucoadhesive vaginal delivery system for nystatin
J. Pharm. Sci.
(2009) - et al.
Mucoadhesive interaction of cysteine grafted poly(2-hydroxyethyl aspartamide) with pig mucin layer of surface plasmon resonance biosensor
J. Ind. Eng. Chem.
(2009) - et al.
Mucoadhesion evaluation of polysaccharide gels for vaginal application by using rheological and indentation measurements
Colloids Surf. B: Biointerfaces
(2012) - et al.
Interaction of chitosan and mucin in a biomembrane model environment
J. Colloid Interface Sci.
(2012) - et al.
Study on the mucoadhesion mechanism of pectin by atomic force microscopy and mucin-particle method
Carbohydr. Polym.
(2010)
A nuclear magnetic resonance approach to the comparison of mucoadhesive properties of polysaccharides for ophthalmic uses
Int. J. Pharm.
An investigation into the role of mucus thickness on mucoadhesion in the gastrointestinal tract of pig
Eur. J. Pharm. Sci.
Mucin biopolymers prevent bacterial aggregation by retaining cells in the free-swimming state
Curr. Biol.
Membrane-tethered mucins have multiple functions on the ocular surface
Exp. Eye Res.
Mucin CYS domains are ancient and highly conserved modules that evolved in concert
Mol. Phylogenet. Evol.
Dimerization of the human MUC2 mucin in the endoplasmic reticulum is followed by a N-glycosylation-dependent transfer of the mono- and dimers to the Golgi apparatus
J. Biol. Chem.
An autocatalytic cleavage in the C terminus of the human MUC2 mucin occurs at the low pH of the late secretory pathway
J. Biol. Chem.
The N terminus of the MUC2 mucin forms trimers that are held together within a trypsin-resistant core fragment
J. Biol. Chem.
Identification of molecular intermediates in the assembly pathway of the MUC5AC mucin
J. Biol. Chem.
Microbial adhesins to gastrointestinal mucus
Trends Microbiol.
Involvement of glycosylation in the intracellular trafficking of glycoproteins in polarized epithelial cells
Biochimie
Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding
J. Biol. Chem.
Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells
J. Biol. Chem.
The MUC1 SEA module is a self-cleaving domain
J. Biol. Chem.
A novel protein derived from the MUC1 gene by alternative splicing and frameshifting
J. Biol. Chem.
Detection of a secreted MUC1/SEC protein by MUC1 isoform specific monoclonal antibodies
Biochem. Biophys. Res. Commun.
Identification of human endomucin-1 and -2 as membrane-bound O-sialoglycoproteins with anti-adhesive activity
FEBS Lett.
Biochemical characterization and molecular cloning of a novel endothelial-specific sialomucin
Blood
Mucin dynamics in intestinal bacterial infection
PLoS ONE
Mucin dynamics and enteric pathogens
Nat. Rev. Microbiol.
Mucins in the gastrointestinal tract in health and disease
Front. Biosci.
Structure and function of the cell surface (tethered) mucins
Annu. Rev. Physiol.
Mucin methods: genes encoding mucins and their genetic variation with a focus on gel-forming mucins
Methods Mol. Biol.
Structure and function of the polymeric mucins in airways mucus
Annu. Rev. Physiol.
The epithelial mucins: structure/function
Roles in Cancer and Inflammatory Diseases
Targeted glycoproteomic identification of biomarkers for human breast carcinoma
J. Proteome Res.
The gastrointestinal mucus system in health and disease
Nat. Rev. Gastroenterol. Hepatol.
The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions
Proc. Natl. Acad. Sci. U. S. A.
Normal but not altered mucins activate neutrophils
Cell Tissue Res.
Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity
J. Immunol.
Role of mucins in inflammatory bowel disease: important lessons from experimental models
Eur. J. Gastroenterol. Hepatol.
Tracheobronchial air-liquid interface cell culture: a model for innate mucosal defense of the upper airways?
Am. J. Physiol. Lung Cell. Mol. Physiol.
Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine
Proc. Natl. Acad. Sci. U. S. A.
Helicobacter pylori vaccines and mechanisms of effective immunity: is mucus the key?
Immunol. Cell Biol.
MUC1 and the immunobiology of cancer
J. Mammary Gland Biol. Neoplasia
Mucoadhesive drug delivery system: an overview
J. Adv. Pharm. Technol. Res.
Adhesion of microorganisms to bovine submaxillary mucin coatings: effect of coating deposition conditions
Biofouling
The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma
Clin. Exp. Metastasis
Barrier properties of gastrointestinal mucus to nanoparticle transport
Macromol. Biosci.
Mucoadhesive buccal systems as a novel strategy for anti-inflammatory drugs administration
Antiinflamm. Antiallergy Agents Med. Chem.
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