Airway Surface Liquid and Respiratory Mucus - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 765

airway wall cells, except Muc7, are primarily, but not exclusively, large transmem-
brane glycoproteins that can be released in airway surface liquid after shedding from
the cell surface. In addition, splice variants of Muc1 and Muc4 are secreted [ 1556 ].
Apical mucins (Muc1, Muc4, and Muc16) tethered to the plasma membrane
are involved in shielding the airway epithelium against pathogens as well as in
cellular signaling [ 1512 ]. On the wetted surface, cilium Muc4 density prevents
mucus penetration into the periciliary fluid and provides lubrication through bound
water. In addition, mucin-1 on the cell surface and microvilli of both ciliated and
secretory cells has a cytoplasmic tail capable of intracellular signaling. It modulates
airway defense and inflammation. Mucin-16, the largest mucin, is expressed by both
ciliated and secretory cells.
Mucin-1 extends at least 100 nm from the cell surface; Muc4 at least 300 nm
[ 1512 ]. Both the MUC1 and MUC4 genes encode heterodimers that are post-
translationally processed. In the lung, Muc1 localizes mainly around microvilli,
whereas Muc4 and Muc16 are expressed on the surface of cilia [ 1512 ]. Functions
of Muc1, Muc4, and Muc16, like those of extracellular mucins, comprise hydration,
lubrication, protection from proteases, and defense against pathogens.
Mucus mesh is composed primarily of entangled mucins and other mucus
constituents with reversible linkages rather than crosslinked polymers, as mucus
sample can reach complete dissolution in saline and recover its viscous and elastic
properties within seconds, when it bears shearing, whereas gels characterized
by covalently crosslinked constituents do not dissolve and irreversibly tear upon
shear [ 1557 ]. Nevertheless, low-affinity non-covalent bonds and stronger disulfide
links exist between mucin fibers as well as other mucus constituents.
Mucins are enriched in serine and threonine that are sites for attachment
to N acetylgalactosamine. Other mucin-linked oligosaccharides comprise N
acetylglucosamine, galactose, fucose, and sialic acids [ 1556 ]. Oligosaccharide
diversity enhances the probability that bacteria bind to mucus for removal by
mucociliary clearance.
Mucin Muc5ac is predominantly produced by goblet cells, whereas Muc5b is
mainly synthesized by mucous cells of submucosal glands [ 1556 ]. Production of
Muc5ac can also occur in glandular mucous cells, whereas synthesis of Muc5b and
Muc2 is detected in goblet cells. Sites of formation of various Muc5b glycoform
types remain unknown.
Mucins can have both anti- and pro-adhesive capacities. The extended structure
of mucins creates steric hindrance, in addition to act as an electrostatic barrier.
However, Muc1 and Muc16 provide binding sites for various types of adhesion
molecules (e.g., ICAM1 and selectins) [ 1512 ].
Between-mucin interactions (e.g., Muc1-ICAM1 connection) can bridge differ-
ent cell types. These associations rapidly elevate cytosolic calcium concentration in
Muc1 cells. The cell response involves Src, PI3K, and PLC enzymes [ 1512 ].

The cytoplasmic tail of mucin-1 influences multiple signaling axes, especially
upon phosphorylation by Src, HER receptors, GSK3

+

β ,andPKC δ [ 1512 ]. Other

binding partners encompass catenin- δ 1, β -catenin and its controller the tumor