-
MBio Nov 2020Mucus plays a pivotal role in protecting the respiratory tract against microbial infections. It acts as a primary contact site to entrap microbes and facilitates their... (Review)
Review
Mucus plays a pivotal role in protecting the respiratory tract against microbial infections. It acts as a primary contact site to entrap microbes and facilitates their removal from the respiratory tract via the coordinated beating of motile cilia. The major components of airway mucus are heavily -glycosylated mucin glycoproteins, divided into gel-forming mucins and transmembrane mucins. The gel-forming mucins MUC5AC and MUC5B are the primary structural components of airway mucus, and they enable efficient clearance of pathogens by mucociliary clearance. MUC5B is constitutively expressed in the healthy airway, whereas MUC5AC is upregulated in response to inflammatory challenge. MUC1, MUC4, and MUC16 are the three major transmembrane mucins of the respiratory tracts which prevent microbial invasion, can act as releasable decoy receptors, and activate intracellular signal transduction pathways. Pathogens have evolved virulence factors such as adhesins that facilitate interaction with specific mucins and mucin glycans, for example, terminal sialic acids. Mucin expression and glycosylation are dependent on the inflammatory state of the respiratory tract and are directly regulated by proinflammatory cytokines and microbial ligands. Gender and age also impact mucin glycosylation and expression through the female sex hormone estradiol and age-related downregulation of mucin production. Here, we discuss what is currently known about the role of respiratory mucins and their glycans during bacterial and viral infections of the airways and their relevance for the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the impact of microbe-mucin interaction in the respiratory tract could inspire the development of novel therapies to boost mucosal defense and combat respiratory infections.
Topics: Bacterial Infections; COVID-19; Glycoproteins; Glycosylation; Humans; Mucin 5AC; Mucin-1; Mucin-5B; Mucins; Respiratory Tract Infections; SARS-CoV-2; Virus Diseases
PubMed: 33184103
DOI: 10.1128/mBio.02374-20 -
Frontiers in Immunology 2023The colonic mucus bilayer is the first line of innate host defense that at the same time houses and nourishes the commensal microbiota. The major components of mucus...
The colonic mucus bilayer is the first line of innate host defense that at the same time houses and nourishes the commensal microbiota. The major components of mucus secreted by goblet cells are MUC2 mucin and the mucus-associated protein, FCGBP (IgGFc-binding protein). In this study, we determine if FCGBP and MUC2 mucin were biosynthesized and interacted together to spatially enhance the structural integrity of secreted mucus and its role in epithelial barrier function. MUC2 and FCGBP were coordinately regulated temporally in goblet-like cells and in response to a mucus secretagogue but not in CRISPR-Cas9 gene-edited cells. Whereas ~85% of MUC2 was colocalized with FCGBP in mucin granules, ~50% of FCGBP was diffusely distributed in the cytoplasm of goblet-like cells. STRING-db v11 analysis of the mucin granule proteome revealed no protein-protein interaction between MUC2 and FCGBP. However, FCGBP interacted with other mucus-associated proteins. FCGBP and MUC2 interacted via N-linked glycans and were non-covalently bound in secreted mucus with cleaved low molecular weight FCGBP fragments. In , cytoplasmic FCGBP was significantly increased and diffusely distributed in wounded cells that healed by enhanced proliferation and migration within 2 days, whereas, in WT cells, MUC2 and FCGBP were highly polarized at the wound margin which impeded wound closure by 6 days. In DSS colitis, restitution and healed lesions in but not littermates, were accompanied by a rapid increase in mRNA and delayed protein expression at 12- and 15-days post DSS, implicating a potential novel endogenous protective role for FCGBP in wound healing to maintain epithelial barrier function.
Topics: Colitis; Goblet Cells; Mucins; Wound Healing; Animals; Mice
PubMed: 37359538
DOI: 10.3389/fimmu.2023.1211336 -
International Journal of Molecular... Jun 2019Mycotoxins, which are widely found in feed ingredients and human food, can exert harmful effects on animals and pose a serious threat to human health. As the first... (Review)
Review
Mycotoxins, which are widely found in feed ingredients and human food, can exert harmful effects on animals and pose a serious threat to human health. As the first barrier against external pollutants, the intestinal mucosa is protected by a mechanical barrier, chemical barrier, immune barrier, and biological barrier. Firstly, mycotoxins can disrupt the mechanical barrier function of the intestinal mucosa, by destroying the morphology and tissue integrity of the intestinal epithelium. Secondly, mycotoxins can cause changes in the composition of mucin monosaccharides and the expression of intestinal mucin, which in turn affects mucin function. Thirdly, mycotoxins can cause damage to the intestinal mucosal immune barrier function. Finally, the microbiotas of animals closely interact with ingested mycotoxins. Based on existing research, this article reviews the effects of mycotoxins on the intestinal mucosal barrier and its mechanisms.
Topics: Animals; Humans; Immunity, Innate; Intestinal Mucosa; Mucins; Mycotoxins
PubMed: 31174254
DOI: 10.3390/ijms20112777 -
Glycobiology Jun 2021The gut microbiota plays a major role in human health and an alteration in gut microbiota structure and function has been implicated in several diseases. In the colon,... (Review)
Review
The gut microbiota plays a major role in human health and an alteration in gut microbiota structure and function has been implicated in several diseases. In the colon, mucus covering the epithelium is critical to maintain a homeostatic relationship with the gut microbiota by harboring a microbial community at safe distance from the epithelium surface. The mucin glycans composing the mucus layer provide binding sites and a sustainable source of nutrients to the bacteria inhabiting the mucus niche. Access to these glycan chains requires a complement of glycoside hydrolases (GHs) produced by bacteria across the phyla constituting the human gut microbiota. Due to the increased recognition of the role of mucus-associated microbes in human health, how commensal bacteria breakdown and utilize host mucin glycans has become of increased interest and is reviewed here. This short review provides an overview of the strategies evolved by gut commensal bacteria to access this rich source of the nutrient with a focus on the GHs involved in mucin degradation.
Topics: Colon; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Mucins; Polysaccharides
PubMed: 33043970
DOI: 10.1093/glycob/cwaa097 -
Respiratory Research Nov 2019Mucus secretion and mucociliary transport are essential defense mechanisms of the airways. Deviations in mucus composition and secretion can impede mucociliary transport... (Review)
Review
Mucus secretion and mucociliary transport are essential defense mechanisms of the airways. Deviations in mucus composition and secretion can impede mucociliary transport and elicit airway obstruction. As such, mucus abnormalities are hallmark features of many respiratory diseases, including asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD). Studying mucus composition and its physical properties has therefore been of significant interest both clinically and scientifically. Yet, measuring mucus production, output, composition and transport presents several challenges. Here we summarize and discuss the advantages and limitations of several techniques from five broadly characterized strategies used to measure mucus secretion, composition and mucociliary transport, with an emphasis on the gel-forming mucins. Further, we summarize advances in the field, as well as suggest potential areas of improvement moving forward.
Topics: Animals; Bronchoscopy; Humans; Mucins; Mucociliary Clearance; Mucus; Respiration Disorders
PubMed: 31752894
DOI: 10.1186/s12931-019-1239-z -
Biomacromolecules Apr 2019Binding of small molecules to mucus membranes in the body has an important role in human health, as it can affect the diffusivity and activity of any molecule that acts...
Binding of small molecules to mucus membranes in the body has an important role in human health, as it can affect the diffusivity and activity of any molecule that acts in a mucosal environment. The binding of drugs and of toxins and signaling molecules from mucosal pathogens is of particular clinical interest. Despite the importance of mucus-small molecule binding, there is a lack of data revealing the precise chemical features of small molecules that lead to mucus binding. We developed a novel equilibrium dialysis assay to measure the binding of libraries of small molecules to mucin and other mucus components, substantially increasing the throughput of small molecule binding measurements. We validated the biological relevance of our approach by quantifying binding of the antibiotic colistin to mucin, and showing that this binding was associated with inhibition of colistin's bioactivity. We next used a small molecule microarray to identify 2,4-diaminopyrimidine as a mucin binding motif and confirmed the importance of this motif for mucin binding using equilibrium dialysis. Furthermore, we showed that, for molecules with this motif, binding to mucins and the mucus-associated biopolymers DNA and alginate is modulated by differences in hydrophobicity and charge. Finally, we showed that molecules lacking the motif exhibited different binding trends from those containing the motif. These results open up the prospect of routine testing of small molecule binding to mucus and optimization of drugs for clinically relevant mucus binding properties.
Topics: Amino Acid Motifs; Animals; DNA; Humans; Hydrophobic and Hydrophilic Interactions; Mucins; Mucous Membrane
PubMed: 30779551
DOI: 10.1021/acs.biomac.8b01467 -
Annals of the American Thoracic Society Nov 2018Mucociliary clearance is a crucial component of innate defense of the lung. In respiratory diseases, such as asthma, chronic obstructive pulmonary disease, and cystic... (Review)
Review
Mucociliary clearance is a crucial component of innate defense of the lung. In respiratory diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis, mucus with abnormal properties contributes to obstruction of the airways. The failure in function of mucus in airway clearance and pathogen protection leads to chronic infection and risk of death. Polymeric mucins (MUC5AC and MUC5B) provide the structural framework of the airway mucus gel. The intracellular synthesis and assembly of these enormous, polymeric O-linked glycoproteins is a complex, multistage process involving intra- and intermolecular disulfide bond formation and extensive addition of O-glycan chains. The fully formed polymers are packaged in a highly organized and condensed form within secretory granules inside specialized secretory cells, and after the appropriate stimulus, mucins are released and expand to form mucus. This short article brings together the current knowledge on the different steps in the production of mucin polymers and the molecular mechanisms that condense them into a packaged form in secretory granules. It is by unraveling the molecular mechanisms that control intracellular mucin supramolecular structure that we might gain new insight into what determines mucus gel properties in health and disease.
Topics: Humans; Lung Diseases; Mucins; Mucociliary Clearance; Secretory Vesicles
PubMed: 30431345
DOI: 10.1513/AnnalsATS.201802-143AW -
PeerJ 2022Mucins are part of the glycoprotein family and the main proteinaceous component of mucus. The sea anemone species, (Phylum Cnidaria) produce large amounts of mucus,...
BACKGROUND
Mucins are part of the glycoprotein family and the main proteinaceous component of mucus. The sea anemone species, (Phylum Cnidaria) produce large amounts of mucus, which have not been studied in detail. Furthermore, there has only been limited investigation of mucin genes in phylum Cnidaria. Therefore, the aim of current study was to identify and analyse the repertoire mucin genes present in and range of other sea anemone species to document their diversity in this group.
METHODS
To achieve this aim, we undertook transcriptome sequencing, assembly, and annotation to identify mucin genes in .
RESULTS
The results from this study demonstrated a diverse repertoire of mucin proteins, including mucin1-like, mucin4-like, and a range of mucin-like genes in the range of sea anemone species examined. The domain structure of the identified mucin genes was found to be consistent with the conserved domains found in the homologous proteins of vertebrate species. The discovery of a diverse range of mucin genes in sea anemone species provided a basic reference for future mucin studies in cnidarians and could lead to research into their application in the pharmacological, clinical, and cosmetic industries.
Topics: Animals; Sea Anemones; Mucins; Proteins; Vertebrates
PubMed: 35539013
DOI: 10.7717/peerj.13292 -
Frontiers in Cellular and Infection... 2022The mucosal surfaces that form the boundary between the external environment and the underlying tissue are protected by a mucus barrier. Mucin glycoproteins, both... (Review)
Review
The mucosal surfaces that form the boundary between the external environment and the underlying tissue are protected by a mucus barrier. Mucin glycoproteins, both secreted and cell surface mucins, are the major components of the barrier. They can exclude pathogens and toxins while hosting the commensal bacteria. In this review, we highlight the dynamic function of the mucins and mucus during infection, how this mucosal barrier is regulated, and how pathogens have evolved mechanisms to evade this defence system.
Topics: Bacteria; Glycoproteins; Mucins; Mucous Membrane; Mucus
PubMed: 35774401
DOI: 10.3389/fcimb.2022.856962 -
G3 (Bethesda, Md.) Jul 2022Epithelia exposed to elements of the environment are protected by a mucus barrier in mammals. This barrier also serves to lubricate during organ movements and to mediate...
Epithelia exposed to elements of the environment are protected by a mucus barrier in mammals. This barrier also serves to lubricate during organ movements and to mediate substance exchanges between the environmental milieu and internal organs. A major component of the mucus barrier is a class of glycosylated proteins called Mucin. Mucin and mucin-related proteins are widely present in the animal kingdom. Mucin mis-regulation has been reported in many diseases such as cancers and ones involving the digestive and respiratory tracts. Although the biophysical properties of isolated Mucins have been extensively studied, in vivo models remain scarce for the study of their functions and regulations. Here, we characterize the Mucin-like JiangShi protein and its mutations in the fruit fly Drosophila. JiangShi is an extracellular glycoprotein with domain features reminiscent of mammalian nonmembranous Mucins, and one of the most widely distributed Mucin-like proteins studied in Drosophila. Both loss and over-production of JiangShi lead to terminal defects in adult structures and organismal death. Although the physiological function of JiangShi remains poorly defined, we present a genetically tractable model system for the in vivo studies of Mucin-like molecules.
Topics: Animals; Drosophila; Glycoproteins; Glycosylation; Mammals; Mucins; Respiratory System
PubMed: 35595239
DOI: 10.1093/g3journal/jkac126