Mucins and Their Role in Shaping the Functions of Mucus Barriers

Abstract

We review what is currently understood about how the structure of the primary solid component of mucus, the glycoprotein mucin, gives rise to the mechanical and biochemical properties of mucus that are required for it to perform its diverse physiological roles. Macroscale processes such as lubrication require mucus of a certain stiffness and spinnability, which are set by structural features of the mucin network, including the identity and density of cross-links and the degree of glycosylation. At the microscale, these same features affect the mechanical environment experienced by small particles and play a crucial role in establishing an interaction-based filter. Finally, mucin glycans are critical for regulating microbial interactions, serving as receptor binding sites for adhesion, as nutrient sources, and as environmental signals. We conclude by discussing how these structural principles can be used in the design of synthetic mucin-mimetic materials and provide suggestions for directions of future work in this field.

Keywords: microbiological interactions; mucin; mucus; permeability; rheology; structure.

Figure 1

Epithelial surfaces of the body coated by mucus, with characteristic pH levels. Figure adapted from Frenkel & Ribbeck (2015a).

Figure 2

(a,b) Schematics of the general structure of (a) secreted and (b) tethered mucin molecules. (c) An illustration of the network established by the gel-forming, secreted mucins. Individual mucin subunits associate via end-to-end disulfide bonds to form even larger macromonomer chains. The network is formed from reversible associations such as hydrophobic interactions between the nonglycosylated, cysteine-rich regions of the molecules and is stabilized by electrostatic repulsion between the charged sugar side chains. Abbreviation: PTS domain, proline, threonine, and/or serine domain. Panels a and b adapted from Bansil & Turner (2006), Dekker et al. (2002), and McGuckin et al. (2011) with permission from Elsevier and Springer Nature. Panel c adapted with permission from Wagner et al. (2017). Copyright 2017, American Chemical Society.

Figure 3

Scanning electron microscopy (SEM) reveals structural changes to mucins associated with different purification processes. (a) MUC5AC mucin purified from pig gastric mucus by the Ribbeck lab. (b) Industrially purified porcine gastric mucin supplied by Sigma-Aldrich.

Figure 4

Microbial interactions with the mucus environment influence pathogenicity, (a) Mucus accommodates a great diversity of microbes and protect against epithelial adhesion and cytotoxicity by pathogenic microbes. Dysregulation of mucus or changes in mucus properties are associated with dysbiosis and susceptibility to infection. (b) Key structural properties of mucins are hypothesized to shape microbiological behavior within mucus and the three-dimensional mucin network. For example, the barrier properties of mucus can limit the diffusion of microbial signaling molecules or toxins through an environment. This can result in signal gradients that promote or interfere with intercellular communications, which may ultimately influence community-level behaviors or facilitate interactions not possible in an unstructured environment. In addition, mucin-associated glycans may serve as chemical signals that attenuate microbial virulence.

Figure 5

Proposed variations in the structure of synthetic mucin molecules to achieve specific functionalities in the contexts of (a) stiffness, (b) spinnability, (c) microscopic viscoelastic response and microstructure, (d) permeability, and (e) microbiological interactions. These variations will further elucidate the relationship between mucin structure and function and the specificity of glycan substructure. Studies of synthetic mucins may focus on how variations in the geometry of presenting a given glycan (e.g., polymer length and branching; grafting density) influence functionality. Studies with varied complex glycan compositions may reveal substructural portions of glycans required for activity. Glycan symbol nomenclature: yellow square, GalNAC; blue square, GlcNAc; yellow circle, galactose; purple triangle, fucose; purple diamond, Neu5Ac; red square, generic mucin sugar.