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Cell Host & Microbe Jul 2023The colon mucus layer is organized with an inner colon mucus layer that is impenetrable to bacteria and an outer mucus layer that is expanded to allow microbiota... (Review)
Review
The colon mucus layer is organized with an inner colon mucus layer that is impenetrable to bacteria and an outer mucus layer that is expanded to allow microbiota colonization. A major component of mucus is MUC2, a glycoprotein that is extensively decorated, especially with O-glycans. In the intestine, goblet cells are specialized in controlling glycosylation and making mucus. Some microbiota members are known to encode multiple proteins that are predicted to bind and/or cleave mucin glycans. The interactions between commensal microbiota and host mucins drive intestinal colonization, while at the same time, the microbiota can utilize the glycans on mucins and affect the colonic mucus properties. This review will examine this interaction between commensal microbes and intestinal mucins and discuss how this interplay affects health and disease.
Topics: Intestinal Mucosa; Mucin-2; Intestines; Mucus; Mucins; Microbiota; Polysaccharides
PubMed: 37442097
DOI: 10.1016/j.chom.2023.05.026 -
Advanced Drug Delivery Reviews Feb 2023Mucins represent a largely untapped class of polymeric building block for biomaterials, therapeutics, and other biotechnology. Because the mucin polymer backbone is... (Review)
Review
Mucins represent a largely untapped class of polymeric building block for biomaterials, therapeutics, and other biotechnology. Because the mucin polymer backbone is genetically encoded, sequence-specific mucins with defined physical and biochemical properties can be fabricated using recombinant technologies. The pendent O-glycans of mucins are increasingly implicated in immunomodulation, suppression of pathogen virulence, and other biochemical activities. Recent advances in engineered cell production systems are enabling the scalable synthesis of recombinant mucins with precisely tuned glycan side chains, offering exciting possibilities to tune the biological functionality of mucin-based products. New metabolic and chemoenzymatic strategies enable further tuning and functionalization of mucin O-glycans, opening new possibilities to expand the chemical diversity and functionality of mucin building blocks. In this review, we discuss these advances, and the opportunities for engineered mucins in biomedical applications ranging from in vitro models to therapeutics.
Topics: Humans; Mucins; Polysaccharides; Biotechnology
PubMed: 36375719
DOI: 10.1016/j.addr.2022.114618 -
Advanced Drug Delivery Reviews Dec 2022Mucin glycoproteins are the major component of mucus and coat epithelial cell surfaces forming the glycocalyx. The glycocalyx and mucus are involved in the transport of... (Review)
Review
Mucin glycoproteins are the major component of mucus and coat epithelial cell surfaces forming the glycocalyx. The glycocalyx and mucus are involved in the transport of nutrients, drugs, gases, and pathogens toward the cell surface. Mucins are also involved in diverse diseases such as cystic fibrosis and cancer. Due to inherent heterogeneity in native mucin structure, many synthetic materials have been designed to probe mucin chemistry, biology, and physics. Such materials include various glycopolymers, low molecular weight glycopeptides, glycopolypeptides, polysaccharides, and polysaccharide-protein conjugates. This review highlights advances in the area of design and synthesis of mucin mimic materials, and their biomedical applications in glycan binding, epithelial models of infection, therapeutic delivery, vaccine formulation, and beyond.
Topics: Humans; Mucins; Mucus; Cystic Fibrosis; Polysaccharides; Glycopeptides
PubMed: 36228896
DOI: 10.1016/j.addr.2022.114540 -
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 -
Molecules (Basel, Switzerland) Oct 2023Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the... (Review)
Review
Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the human body, which can be classified into secreted mucins and transmembrane mucins according to their distributions. The major difference between them is that secreted mucins do not have transmembrane structural domains, and the expression of each mucin is organ and cell-specific. Under physiological conditions, mucin glycans are involved in the composition of the mucus barrier and thus protect the body from infection and injury. However, abnormal expression of mucin glycans can lead to the occurrence of diseases, especially cancer, through various mechanisms. Therefore, targeting mucin glycans for the diagnosis and treatment of cancer has always been a promising research direction. Here, we first summarize the main types of glycosylation (O-GalNAc glycosylation and N-glycosylation) on mucins and the mechanisms by which abnormal mucin glycans occur. Next, how abnormal mucin glycans contribute to cancer development is described. Finally, we summarize MUC1-based antibodies, vaccines, radio-pharmaceuticals, and CAR-T therapies using the best characterized MUC1 as an example. In this section, we specifically elaborate on the recent new cancer therapy CAR-M, which may bring new hope to cancer patients.
Topics: Humans; Mucins; Mucin-1; Polysaccharides; Glycosylation; Neoplasms
PubMed: 37894512
DOI: 10.3390/molecules28207033 -
Advanced Drug Delivery Reviews May 2022The secreted mucus layer that lines and protects epithelial cells is conserved across diverse species. While the exact composition of this protective layer varies... (Review)
Review
The secreted mucus layer that lines and protects epithelial cells is conserved across diverse species. While the exact composition of this protective layer varies between organisms, certain elements are conserved, including proteins that are heavily decorated with N-acetylgalactosamine-based sugars linked to serines or threonines (O-linked glycosylation). These heavily O-glycosylated proteins, known as mucins, exist in many forms and are able to form hydrated gel-like structures that coat epithelial surfaces. In vivo studies in diverse organisms have highlighted the importance of both the mucin proteins as well as their constituent O-glycans in the protection and health of internal epithelia. Here, we summarize in vivo approaches that have shed light on the synthesis and function of these essential components of mucus.
Topics: Epithelial Cells; Glycosylation; Humans; Mucins; Mucus; Polysaccharides
PubMed: 35278522
DOI: 10.1016/j.addr.2022.114182 -
Biochemical Society Transactions Oct 2018Mucus plays a vital role in protecting the lungs from environmental factors, but conversely, in muco-obstructive airway disease, mucus becomes pathologic. In its... (Review)
Review
Mucus plays a vital role in protecting the lungs from environmental factors, but conversely, in muco-obstructive airway disease, mucus becomes pathologic. In its protective role, mucus entraps microbes and particles removing them from the lungs via the co-ordinated beating of motile cilia. This mechanism of lung defence is reliant upon a flowing mucus gel, and the major macromolecular components that determine the rheological properties of mucus are the polymeric mucins, MUC5AC and MUC5B. These large O-linked glycoproteins have direct roles in maintaining lung homeostasis. MUC5B is essential for interaction with the ciliary clearance system and MUC5AC is up-regulated in response to allergic inflammatory challenge. Mucus with abnormal biophysical properties is a feature of muco-obstructive respiratory disease and can result from many different mechanisms including alterations in mucin polymer assembly, mucin concentration and the macromolecular form in mucus, as well as changes in airway surface hydration, pH and ion composition. The abnormal mucus results in defective lung protection via compromised ciliary clearance, leading to infection and inflammation.
Topics: Animals; Glycoproteins; Glycosylation; Homeostasis; Humans; Hypersensitivity; Inflammation; Lung; Macromolecular Substances; Mice; Mucin 5AC; Mucin-5B; Mucins; Polymers; Polysaccharides; Respiration Disorders; Respiratory System; Rheology
PubMed: 30154090
DOI: 10.1042/BST20170402 -
The Journal of Clinical Investigation Oct 2023The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the...
The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and noninflamed samples from patients with inflammatory bowel disease (IBD) undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF/CFTR signaling axis in the adult intestine and identify epithelial cell-derived TNF as an upstream regulator of mucin homeostasis.
Topics: Humans; Animals; Mice; Mucins; Cystic Fibrosis Transmembrane Conductance Regulator; Tumor Necrosis Factor Inhibitors; Epithelial Cells; Cell Differentiation; Tumor Necrosis Factors; Homeostasis
PubMed: 37643009
DOI: 10.1172/JCI163591 -
Physiological Reviews Jan 2006This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (> or =50%... (Review)
Review
This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (> or =50% carbohydrate, wt/wt). MUC protein backbones are characterized by numerous tandem repeats that contain proline and are high in serine and/or threonine residues, the sites of O-glycosylation. Secretory and membrane-tethered mucins contribute to mucociliary defense, an innate immune defense system that protects the airways against pathogens and environmental toxins. Inflammatory/immune response mediators and the overproduction of mucus characterize chronic airway diseases: asthma, chronic obstructive pulmonary diseases (COPD), or cystic fibrosis (CF). Specific inflammatory/immune response mediators can activate mucin gene regulation and airway remodeling, including goblet cell hyperplasia (GCH). These processes sustain airway mucin overproduction and contribute to airway obstruction by mucus and therefore to the high morbidity and mortality associated with these diseases. Importantly, mucin overproduction and GCH, although linked, are not synonymous and may follow from different signaling and gene regulatory pathways. In section i, structure, expression, and localization of the 18 human MUC genes and MUC gene products having tandem repeat domains and the specificity and application of MUC-specific antibodies that identify mucin gene products in airway tissues, cells, and secretions are overviewed. Mucin overproduction in chronic airway diseases and secretory cell metaplasia in animal model systems are reviewed in section ii and addressed in disease-specific subsections on asthma, COPD, and CF. Information on regulation of mucin genes by inflammatory/immune response mediators is summarized in section iii. In section iv, deficiencies in understanding the functional roles of mucins at the molecular level are identified as areas for further investigations that will impact on airway health and disease. The underlying premise is that understanding the pathways and processes that lead to mucus overproduction in specific airway diseases will allow circumvention or amelioration of these processes.
Topics: Animals; Glycoproteins; Humans; Lung; Mucins; Respiratory System; Respiratory Tract Diseases
PubMed: 16371599
DOI: 10.1152/physrev.00010.2005 -
Nature Chemical Biology Jul 2022Mucins are large gel-forming polymers inside the mucus barrier that inhibit the yeast-to-hyphal transition of Candida albicans, a key virulence trait of this important...
Mucins are large gel-forming polymers inside the mucus barrier that inhibit the yeast-to-hyphal transition of Candida albicans, a key virulence trait of this important human fungal pathogen. However, the molecular motifs in mucins that inhibit filamentation remain unclear despite their potential for therapeutic interventions. Here, we determined that mucins display an abundance of virulence-attenuating molecules in the form of mucin O-glycans. We isolated and cataloged >100 mucin O-glycans from three major mucosal surfaces and established that they suppress filamentation and related phenotypes relevant to infection, including surface adhesion, biofilm formation and cross-kingdom competition between C. albicans and the bacterium Pseudomonas aeruginosa. Using synthetic O-glycans, we identified three structures (core 1, core 1 + fucose and core 2 + galactose) that are sufficient to inhibit filamentation with potency comparable to the complex O-glycan pool. Overall, this work identifies mucin O-glycans as host molecules with untapped therapeutic potential to manage fungal pathogens.
Topics: Candida albicans; Fucose; Mucins; Polysaccharides; Virulence
PubMed: 35668191
DOI: 10.1038/s41589-022-01035-1