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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 -
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... Mar 2019MUC5AC and MUC5B are the predominant gel-forming mucins in the mucus layer of human airways. Each mucin has distinct functions and site-specific expression. However, the...
RATIONALE
MUC5AC and MUC5B are the predominant gel-forming mucins in the mucus layer of human airways. Each mucin has distinct functions and site-specific expression. However, the regional distribution of expression and cell types that secrete each mucin in normal/healthy human airways are not fully understood.
OBJECTIVES
To characterize the regional distribution of MUC5B and MUC5AC in normal/healthy human airways and assess which cell types produce these mucins, referenced to the club cell secretory protein (CCSP).
METHODS
Multiple airway regions from 16 nonsmoker lungs without a history of lung disease were studied. MUC5AC, MUC5B, and CCSP expression/colocalization were assessed by RNA in situ hybridization and immunohistochemistry in five lungs with histologically healthy airways. Droplet digital PCR and cell cultures were performed for absolute quantification of MUC5AC/5B ratios and protein secretion, respectively.
MEASUREMENTS AND MAIN RESULTS
Submucosal glands expressed MUC5B, but not MUC5AC. However, MUC5B was also extensively expressed in superficial epithelia throughout the airways except for the terminal bronchioles. Morphometric calculations revealed that the distal airway superficial epithelium was the predominant site for MUC5B expression, whereas MUC5AC expression was concentrated in proximal, cartilaginous airways. RNA in situ hybridization revealed MUC5AC and MUC5B were colocalized with CCSP-positive secretory cells in proximal superficial epithelia, whereas MUC5B and CCSP-copositive cells dominated distal regions.
CONCLUSIONS
In normal/healthy human airways, MUC5B is the dominant secretory mucin in the superficial epithelium and glands, with distal airways being a major site of expression. MUC5B and MUC5AC expression is a property of CCSP-positive secretory cells in superficial airway epithelia.
Topics: Humans; Lung; Mucin 5AC; Mucin-5B; Protein Transport; Respiratory Physiological Phenomena
PubMed: 30352166
DOI: 10.1164/rccm.201804-0734OC -
Cell Host & Microbe Jul 2017Host factors in the intestine help select for bacteria that promote health. Certain commensals can utilize mucins as an energy source, thus promoting their colonization....
Host factors in the intestine help select for bacteria that promote health. Certain commensals can utilize mucins as an energy source, thus promoting their colonization. However, health conditions such as inflammatory bowel disease (IBD) are associated with a reduced mucus layer, potentially leading to dysbiosis associated with this disease. We characterize the capability of commensal species to cleave and transport mucin-associated monosaccharides and identify several Clostridiales members that utilize intestinal mucins. One such mucin utilizer, Peptostreptococcus russellii, reduces susceptibility to epithelial injury in mice. Several Peptostreptococcus species contain a gene cluster enabling production of the tryptophan metabolite indoleacrylic acid (IA), which promotes intestinal epithelial barrier function and mitigates inflammatory responses. Furthermore, metagenomic analysis of human stool samples reveals that the genetic capability of microbes to utilize mucins and metabolize tryptophan is diminished in IBD patients. Our data suggest that stimulating IA production could promote anti-inflammatory responses and have therapeutic benefits.
Topics: Animals; Anti-Inflammatory Agents; Bacteria; Bacteroides; Clostridiales; Colon; Cytokines; Dysbiosis; Humans; Indoles; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Mice; Mucin-2; Mucins; Organoids; Peptostreptococcus; Symbiosis
PubMed: 28704649
DOI: 10.1016/j.chom.2017.06.007 -
Annals of the American Thoracic Society Nov 2018Exocytosis of secreted mucins is the final step in their intracellular processing, resulting in their release into the airway lumen to interact with water and ions to... (Review)
Review
Exocytosis of secreted mucins is the final step in their intracellular processing, resulting in their release into the airway lumen to interact with water and ions to form mucus. Mucins are secreted at a low baseline rate and a high stimulated rate, and both rates are regulated by second messengers acting on components of the exocytic machinery. The principal physiologic function of the low baseline rate is to support steady-state mucociliary clearance of inhaled particles and pathogens that enter the airways during normal breathing. Even in the setting of mucin hyperproduction, baseline secretion generally does not induce mucus occlusion. The principal physiologic function of the high stimulated rate of secretion from both submucosal glands and surface goblet cells in proximal airways appears to be to sweep away larger particles, whereas in distal airways it appears to act in concert with mucin hyperproduction to induce mucus occlusion to trap migrating helminths. Pathophysiologically, stimulated mucin secretion in the setting of mucin hyperproduction from allergic or other types of airway inflammation in the absence of helminth infection causes airflow obstruction and infection. Molecular components of the mucin exocytic machinery are increasingly being identified, and surprisingly, many components are not shared between baseline and stimulated machines. The physiologic significance of the presence of two distinct molecular machines is not yet known, such as whether these interact selectively with secretory granules of different sizes or contents. A full understanding of the mechanism and regulation of airway mucin secretion will provide further insight into pathophysiologic processes and may identify therapeutic strategies to alleviate obstructive airway diseases.
Topics: Exocytosis; Humans; Lung Diseases; Mucins; Mucociliary Clearance; Mucus; Respiratory Mucosa; Secretory Vesicles
PubMed: 30431339
DOI: 10.1513/AnnalsATS.201806-371AW -
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 -
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