Review
Mucins: A biologically relevant glycan barrier in mucosal protection

https://doi.org/10.1016/j.bbagen.2014.05.003Get rights and content

Highlights

  • Mucins are glycoproteins expressed on all mucosal surfaces.

  • Mucin glycobiology defines an array of glycan sequences on mucosal cell surfaces.

  • Mucins exist as secreted and membrane-associated forms.

  • Disease related mucins show abberant peptide and glycan sequences.

Abstract

Background

The mucins found as components of mucus gel layers at mucosal surfaces throughout the body play roles in protection as part of the defensive barrier on an organ and tissue specific basis.

Scope of the review

The human MUC gene family codes up to 20 known proteins, which can be divided into secreted and membrane-associated forms each with a typical protein domain structure. The secreted mucins are adapted to cross link in order to allow formation of the extended mucin networks found in the secreted mucus gels. The membrane-associated mucins possess membrane specific domains which enable their various biological functions as part of the glycocalyx. All mucins are highly O-glycosylated and this is tissue specific and linked with specific biological functions at these locations. Mucin biology is dynamic and the processes of degradation and turnover are well integrated with biosynthesis to maintain a continuous mucosal protection against all external aggressive forces. Interaction of mucins with microflora plays an important role in normal function. Mucins are modified in a variety of diseases and this may be due to abberant mucin peptide or glycosylation.

Major conclusions

Mucins represent a family of glycoprotein having fundamental roles in mucosal protection and communication with external environment.

General significance

The review emphasises the nature of mucins as glycoproteins and their role in presenting an array of glycan structures at the mucosal cell surface.

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)

  • G. Uccello-Barretta et al.

    A nuclear magnetic resonance approach to the comparison of mucoadhesive properties of polysaccharides for ophthalmic uses

    Int. J. Pharm.

    (2011)
  • F.J.O. Varum et al.

    An investigation into the role of mucus thickness on mucoadhesion in the gastrointestinal tract of pig

    Eur. J. Pharm. Sci.

    (2010)
  • M. Caldara et al.

    Mucin biopolymers prevent bacterial aggregation by retaining cells in the free-swimming state

    Curr. Biol.

    (2012)
  • B. Govindarajan et al.

    Membrane-tethered mucins have multiple functions on the ocular surface

    Exp. Eye Res.

    (2010)
  • J.L. Desseyn

    Mucin CYS domains are ancient and highly conserved modules that evolved in concert

    Mol. Phylogenet. Evol.

    (2009)
  • N. Asker et al.

    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.

    (1998)
  • M.E. Lidell et al.

    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.

    (2003)
  • K. Godl et al.

    The N terminus of the MUC2 mucin forms trimers that are held together within a trypsin-resistant core fragment

    J. Biol. Chem.

    (2002)
  • J.K. Sheehan et al.

    Identification of molecular intermediates in the assembly pathway of the MUC5AC mucin

    J. Biol. Chem.

    (2004)
  • N. Juge

    Microbial adhesins to gastrointestinal mucus

    Trends Microbiol.

    (2012)
  • G. Huet et al.

    Involvement of glycosylation in the intracellular trafficking of glycoproteins in polarized epithelial cells

    Biochimie

    (2003)
  • A. Thathiah et al.

    Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding

    J. Biol. Chem.

    (2003)
  • S.J. Williams et al.

    Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells

    J. Biol. Chem.

    (2001)
  • F. Levitin et al.

    The MUC1 SEA module is a self-cleaving domain

    J. Biol. Chem.

    (2005)
  • F. Levitin et al.

    A novel protein derived from the MUC1 gene by alternative splicing and frameshifting

    J. Biol. Chem.

    (2005)
  • N. Smorodinsky et al.

    Detection of a secreted MUC1/SEC protein by MUC1 isoform specific monoclonal antibodies

    Biochem. Biophys. Res. Commun.

    (1996)
  • M. Kinoshita et al.

    Identification of human endomucin-1 and -2 as membrane-bound O-sialoglycoproteins with anti-adhesive activity

    FEBS Lett.

    (2001)
  • S.M. Morgan et al.

    Biochemical characterization and molecular cloning of a novel endothelial-specific sialomucin

    Blood

    (1999)
  • S.K. Linden et al.

    Mucin dynamics in intestinal bacterial infection

    PLoS ONE

    (2008)
  • M.A. McGuckin et al.

    Mucin dynamics and enteric pathogens

    Nat. Rev. Microbiol.

    (2011)
  • A.P. Corfield et al.

    Mucins in the gastrointestinal tract in health and disease

    Front. Biosci.

    (2001)
  • C.L. Hattrup et al.

    Structure and function of the cell surface (tethered) mucins

    Annu. Rev. Physiol.

    (2008)
  • K. Rousseau et al.

    Mucin methods: genes encoding mucins and their genetic variation with a focus on gel-forming mucins

    Methods Mol. Biol.

    (2012)
  • D.J. Thornton et al.

    Structure and function of the polymeric mucins in airways mucus

    Annu. Rev. Physiol.

    (2008)
  • I. Van Seuningen

    The epithelial mucins: structure/function

    Roles in Cancer and Inflammatory Diseases

    (2008)
  • K.L. Abbott et al.

    Targeted glycoproteomic identification of biomarkers for human breast carcinoma

    J. Proteome Res.

    (2008)
  • M.E. Johansson et al.

    The gastrointestinal mucus system in health and disease

    Nat. Rev. Gastroenterol. Hepatol.

    (2013)
  • M.E. Johansson et al.

    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.

    (2011)
  • M.L. Aknin et al.

    Normal but not altered mucins activate neutrophils

    Cell Tissue Res.

    (2004)
  • C.A. Carlos et al.

    Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity

    J. Immunol.

    (2005)
  • A.W. Einerhand et al.

    Role of mucins in inflammatory bowel disease: important lessons from experimental models

    Eur. J. Gastroenterol. Hepatol.

    (2002)
  • M. Kesimer et al.

    Tracheobronchial air-liquid interface cell culture: a model for innate mucosal defense of the upper airways?

    Am. J. Physiol. Lung Cell. Mol. Physiol.

    (2009)
  • V. Lakshminarayanan et al.

    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.

    (2012)
  • P. Sutton

    Helicobacter pylori vaccines and mechanisms of effective immunity: is mucus the key?

    Immunol. Cell Biol.

    (2001)
  • J. Taylor-Papadimitriou et al.

    MUC1 and the immunobiology of cancer

    J. Mammary Gland Biol. Neoplasia

    (2002)
  • B.M. Boddupalli et al.

    Mucoadhesive drug delivery system: an overview

    J. Adv. Pharm. Technol. Res.

    (2010)
  • I.A. Bushnak et al.

    Adhesion of microorganisms to bovine submaxillary mucin coatings: effect of coating deposition conditions

    Biofouling

    (2010)
  • J.A. Cipollone et al.

    The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma

    Clin. Exp. Metastasis

    (2012)
  • J.S. Crater et al.

    Barrier properties of gastrointestinal mucus to nanoparticle transport

    Macromol. Biosci.

    (2010)
  • A. Figueiras et al.

    Mucoadhesive buccal systems as a novel strategy for anti-inflammatory drugs administration

    Antiinflamm. Antiallergy Agents Med. Chem.

    (2011)
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