-
Annual Review of Biochemistry Jun 2020Generating the barriers that protect our inner surfaces from bacteria and other challenges requires large glycoproteins called mucins. These come in two types,... (Review)
Review
Generating the barriers that protect our inner surfaces from bacteria and other challenges requires large glycoproteins called mucins. These come in two types, gel-forming and transmembrane, all characterized by large, highly -glycosylated mucin domains that are diversely decorated by Golgi glycosyltransferases to become extended rodlike structures. The general functions of mucins on internal epithelial surfaces are to wash away microorganisms and, even more importantly, to build protective barriers. The latter function is most evident in the large intestine, where the inner mucus layer separates the numerous commensal bacteria from the epithelial cells. The host's conversion of MUC2 to the outer mucus layer allows bacteria to degrade the mucin glycans and recover the energy content that is then shared with the host. The molecular nature of the mucins is complex, and how they construct the extracellular complex glycocalyx and mucus is poorly understood and a future biochemical challenge.
Topics: Animals; Carbohydrate Conformation; Carbohydrate Sequence; Gastrointestinal Microbiome; Gene Expression; Glycocalyx; Glycosylation; Glycosyltransferases; Goblet Cells; Humans; Mucins; Mucus; Symbiosis
PubMed: 32243763
DOI: 10.1146/annurev-biochem-011520-105053 -
Experimental Eye Research Aug 2020Tears have a vital function to protect and lubricate the ocular surface. Tear production, distribution and clearance is tightly regulated by the lacrimal functional unit... (Review)
Review
Tears have a vital function to protect and lubricate the ocular surface. Tear production, distribution and clearance is tightly regulated by the lacrimal functional unit (LFU) to meet ocular surface demands. The tear film consists of an aqueous-mucin layer, containing fluid and soluble factors produced by the lacrimal glands and mucin secreted by the goblet cells, that is covered by a lipid layer. The array of proteins, glycoproteins and lipids in tears function to maintain a stable, well-lubricated and smooth optical surface. Tear factors also promote wound healing, suppress inflammation, scavenge free radicals, and defend against microbial infection. Disease and dysfunction of the LFU leads to tear instability, increased evaporation, inflammation, and blurred and fluctuating vision. The function of tear components and the consequences of tear deficiency on the ocular surface are reviewed.
Topics: Dry Eye Syndromes; Glycoproteins; Humans; Lacrimal Apparatus; Mucins; Tears
PubMed: 32561483
DOI: 10.1016/j.exer.2020.108115 -
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 -
Bulletin Du Cancer Nov 2022MUC1 is a highly glycosylated transmembrane mucin on the luminal surface of epithelial cells, protecting them from extreme factors. In cancer cells, MUC1 expression is... (Review)
Review
MUC1 is a highly glycosylated transmembrane mucin on the luminal surface of epithelial cells, protecting them from extreme factors. In cancer cells, MUC1 expression is upregulated and the protein structure, glycosylation level and spatial distribution are altered. It was found that upregulated MUC1 is involved in the regulation of several signaling pathways and plays an instrumental role in tumor cell metabolism, apoptosis, epithelial mesenchymal transition and distant metastasis. MUC1 glycosylation insufficiency leads to exposure of novel antigenic epitopes that can be used as specific targets for therapy and diagnosis. In addition, MUC1 was found to be closely related to HIF and can form a positive feedback loop leading to hypoxic malignant tumor progression. Currently, MUC1-based targeted drugs include monoclonal antibodies, antibody-coupled drugs, aptamers and cancer vaccines, some of which have already entered clinical trials. This paper reviews the role and mechanism of MUC1 in the biological function of malignant tumors and describes the potential of MUC1 in tumor-targeted chemotherapy, targeted radiotherapy and diagnostic imaging.
Topics: Humans; Antibodies, Monoclonal; Cancer Vaccines; Epitopes; Glycosylation; Mucin-1; Mucins; Neoplasms
PubMed: 36184332
DOI: 10.1016/j.bulcan.2022.08.001 -
International Journal of Molecular... Jun 2021Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of... (Review)
Review
Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete () and incomplete (, and ) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy.
Topics: Biomarkers, Tumor; Early Detection of Cancer; GATA6 Transcription Factor; Gene Expression Regulation, Neoplastic; Humans; Intestines; Metaplasia; Mucin 5AC; Mucin-2; Mucin-6; Mutation; Prognosis; Stomach Neoplasms; Tumor Suppressor Protein p53
PubMed: 34206291
DOI: 10.3390/ijms22136652 -
American Journal of Respiratory and... Feb 2024Non-cystic fibrosis bronchiectasis (NCFB) may originate in bronchiolar regions of the lung. Accordingly, there is a need to characterize the morphology and molecular...
Non-cystic fibrosis bronchiectasis (NCFB) may originate in bronchiolar regions of the lung. Accordingly, there is a need to characterize the morphology and molecular characteristics of NCFB bronchioles. Test the hypothesis that NCFB exhibits a major component of bronchiolar disease manifest by mucus plugging and ectasia. Morphologic criteria and region-specific epithelial gene expression, measured histologically and by RNA hybridization and immunohistochemistry, identified proximal and distal bronchioles in excised NCFB lungs. RNA hybridization and immunohistochemistry assessed bronchiolar mucus accumulation and mucin gene expression. CRISPR-Cas9-mediated IL-1R1 knockout in human bronchial epithelial cultures tested IL-1α and IL-1β contributions to mucin production. Spatial transcriptional profiling characterized NCFB distal bronchiolar gene expression. Bronchiolar perimeters and lumen areas per section area were increased in proximal, but not distal, bronchioles in NCFB versus control lungs, suggesting proximal bronchiolectasis. In NCFB, mucus plugging was observed in ectatic proximal bronchioles and associated nonectatic distal bronchioles in sections with disease. MUC5AC and MUC5B mucins were upregulated in NCFB proximal bronchioles, whereas MUC5B was selectively upregulated in distal bronchioles. Bronchiolar mucus plugs were populated by IL-1β-expressing macrophages. NCFB sterile sputum supernatants induced human bronchial epithelial MUC5B and MUC5AC expression that was >80% blocked by IL-1R1 ablation. Spatial transcriptional profiling identified upregulation of genes associated with secretory cells, hypoxia, interleukin pathways, and IL-1β-producing macrophages in mucus plugs and downregulation of epithelial ciliogenesis genes. NCFB exhibits distinctive proximal and distal bronchiolar disease. Both bronchiolar regions exhibit bronchiolar secretory cell features and mucus plugging but differ in mucin gene regulation and ectasia.
Topics: Humans; Bronchioles; Dilatation, Pathologic; Bronchiectasis; Cystic Fibrosis; Mucins; Interleukin-1beta; Fibrosis; RNA; Mucin 5AC
PubMed: 38016030
DOI: 10.1164/rccm.202306-1093OC -
Nature Biotechnology Apr 2024Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we...
Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells.
Topics: Animals; Mice; Mucins; Peptide Hydrolases; Neoplasms; Proteolysis
PubMed: 37537499
DOI: 10.1038/s41587-023-01840-6 -
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 -
ChemPlusChem Dec 2020Mucins are bottlebrush biopolymers that are glycoproteins on the surfaces of cells and as hydrogels secreted inside and outside the body. Mucin function in biology... (Review)
Review
Mucins are bottlebrush biopolymers that are glycoproteins on the surfaces of cells and as hydrogels secreted inside and outside the body. Mucin function in biology includes cell-cell recognition, signaling, protection, adhesion, and lubrication. Because of their attractive and diverse properties, mucins have recently become the focus of synthetic efforts by researchers who hope to understand and emulate these biomaterials. This review is focused on the development of methodologies for preparing mucin-inspired synthetic oligomers and glycopolymers, including solid-phase synthesis, polymerization of glycosylated monomers, and post-polymerization grafting of glycans to polymer chains. How these synthetic mucins have been used in health applications is discussed. Natural mucins are formed from a conserved set of monomers that are combined into chains of different sequences and lengths to achieve materials with widely diverse properties. Adopting this design paradigm from natural mucins could lead to next-generation bioinspired synthetic materials.
Topics: Humans; Mucins; Polymers
PubMed: 33346954
DOI: 10.1002/cplu.202000637 -
Methods in Molecular Biology (Clifton,... 2022Mucin glycosylation is the key facilitator of microbial attachment and nutrition and it varies according to biological location, health and disease status, microbiome...
Mucin glycosylation is the key facilitator of microbial attachment and nutrition and it varies according to biological location, health and disease status, microbiome composition, infection, and multiple other factors. Mucin glycans have also been reported to attenuate pathogen virulence and mediate biofilm dispersal. With the labor intensive and time-consuming purification required for natural mucins and their low quantitative yield from biological sources, natural mucin microarrays provide a convenient and multiplexed platform to study mucin glycosylation and interactions. In this chapter we describe the purification of natural mucins, using sputum as an example biological source, and the printing of natural mucin microarrays.
Topics: Glycosylation; Microarray Analysis; Mucins; Polysaccharides; Virulence
PubMed: 34972934
DOI: 10.1007/978-1-0716-2148-6_8