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Cell Oct 2022Mucus protects the epithelial cells of the digestive and respiratory tracts from pathogens and other hazards. Progress in determining the molecular mechanisms of mucus...
Mucus protects the epithelial cells of the digestive and respiratory tracts from pathogens and other hazards. Progress in determining the molecular mechanisms of mucus barrier function has been limited by the lack of high-resolution structural information on mucins, the giant, secreted, gel-forming glycoproteins that are the major constituents of mucus. Here, we report how mucin structures we determined enabled the discovery of an unanticipated protective role of mucus: managing the toxic transition metal copper. Using two juxtaposed copper binding sites, one for Cu and the other for Cu, the intestinal mucin, MUC2, prevents copper toxicity by blocking futile redox cycling and the squandering of dietary antioxidants, while nevertheless permitting uptake of this important trace metal into cells. These findings emphasize the value of molecular structure in advancing mucosal biology, while introducing mucins, produced in massive quantities to guard extensive mucosal surfaces, as extracellular copper chaperones.
Topics: Mucins; Mucin-2; Copper; Intestines; Mucus; Intestinal Mucosa
PubMed: 36206754
DOI: 10.1016/j.cell.2022.09.021 -
Molecular & Cellular Proteomics : MCP May 2017The mucin -glycosylation of 10 individuals with and without gastric disease was examined in depth in order to generate a structural map of human gastric glycosylation....
The mucin -glycosylation of 10 individuals with and without gastric disease was examined in depth in order to generate a structural map of human gastric glycosylation. In the stomach, these mucins and their -glycosylation protect the epithelial surface from the acidic gastric juice and provide the first point of interaction for pathogens such as reported to cause gastritis, gastric and duodenal ulcers and gastric cancer. The rational of the present study was to map the -glycosylation that the pathogen may come in contact with. An enormous diversity in glycosylation was found, which varied both between individuals and within mucins from a single individual: mucin glycan chain length ranged from 2-13 residues, each individual carried 34-103 -glycan structures and in total over 258 structures were identified. The majority of gastric -glycans were neutral and fucosylated. Blood group I antigens, as well as terminal α1,4-GlcNAc-like and GalNAcβ1-4GlcNAc-like (LacdiNAc-like), were common modifications of human gastric -glycans. Furthemore, each individual carried 1-14 glycan structures that were unique for that individual. The diversity and alterations in gastric -glycosylation broaden our understanding of the human gastric -glycome and its implications for gastric cancer research and emphasize that the high individual variation makes it difficult to identify gastric cancer specific structures. However, despite the low number of individuals, we could verify a higher level of sialylation and sulfation on gastric -glycans from cancerous tissue than from healthy stomachs.
Topics: Blood Group Antigens; Chromatography, Liquid; Epitopes; Gastric Mucins; Humans; Mucin 5AC; Polysaccharides; Tandem Mass Spectrometry
PubMed: 28461410
DOI: 10.1074/mcp.M116.067983 -
FASEB Journal : Official Publication of... Feb 2020Many members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to...
Many members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to tumor invasion, metastasis, and immune evasion. The large size and extensive glycosylation present challenges to study the mucin structure using traditional methods, including crystallography. We offer the hypothesis that the functional versatility of mucins may be attributed to the presence of intrinsically disordered regions (IDRs) that provide dynamism and flexibility and that the IDRs offer potential therapeutic targets. Herein, we examined the links between the mucin structure and function based on IDRs, posttranslational modifications (PTMs), and potential impact on their interactome. Using sequence-based bioinformatics tools, we observed that mucins are predicted to be moderately (20%-40%) to highly (>40%) disordered and many conserved mucin domains could be disordered. Phosphorylation sites overlap with IDRs throughout the mucin sequences. Additionally, the majority of predicted O- and N- glycosylation sites in the tandem repeat regions occur within IDRs and these IDRs contain a large number of functional motifs, that is, molecular recognition features (MoRFs), which directly influence protein-protein interactions (PPIs). This investigation provides a novel perspective and offers an insight into the complexity and dynamic nature of mucins.
Topics: Glycosylation; Humans; Models, Molecular; Mucins; Protein Domains; Sequence Analysis, Protein; Structure-Activity Relationship
PubMed: 31908009
DOI: 10.1096/fj.201901898RR -
American Journal of Respiratory and... Mar 2019
Topics: Humans; Mucin 5AC; Mucin-5B; Mucins; Respiratory System
PubMed: 30376352
DOI: 10.1164/rccm.201809-1818ED -
British Journal of Cancer Nov 2004Mucins are members of an expanding family of large multifunctional glycoproteins. Pancreatic mucins have important biological functions, including the protection,... (Review)
Review
Mucins are members of an expanding family of large multifunctional glycoproteins. Pancreatic mucins have important biological functions, including the protection, lubrication, and moisturisation of the surfaces of epithelial tissues lining ductal structures within the pancreas. Several lines of evidence support the notion that deregulated mucin production is a hallmark of inflammatory and neoplastic disorders of the pancreas. Herein, we discuss the factors that contribute to the lethality of pancreatic cancer as well as the key role played by mucins, particularly MUC1 and MUC4, in the development and progression of the disease. Aspects pertaining to the aberrant expression and glycosylation of mucins are discussed, with special emphasis on their potential impact on the design and implementation of adequate diagnostic and therapeutic strategies for combating this lethal malignancy.
Topics: Glycosylation; Humans; Mucin-1; Mucin-4; Mucins; Pancreatic Neoplasms
PubMed: 15494719
DOI: 10.1038/sj.bjc.6602163 -
Pathobiology : Journal of... 2012The purpose of this study was to investigate the expression of MUC1, MUC2, MUC5AC and MUC5B in breast mucinous lesions.
OBJECTIVE
The purpose of this study was to investigate the expression of MUC1, MUC2, MUC5AC and MUC5B in breast mucinous lesions.
METHODS
Immunohistochemical staining of MUC1, MUC2, MUC5AC, MUC5B and synaptophysin was performed in 78 cases of mucinous carcinoma (MC), 36 cases of mucocele-like lesions (MLL) and 13 cases of solid papillary carcinoma (SPC). MC was classified as type A or type B and MLL was classified as MLL, MLL with atypical ductal hyperplasia and MLL with ductal carcinoma in situ.
RESULTS
MUC1 was expressed in MC type A and MLL with luminal/apical pattern, while MC type B and SPC showed membrano-cytoplasmic expression of MUC1 (p < 0.001). A luminal/apical or luminal/apical + cytoplasmic pattern of MUC2 expression was observed in MC type A, while MC type B and SPC showed membrano-cytoplasmic MUC2 expression (p < 0.001). On MUC5B staining, MC type A and MLL were negative, while MC type B and SPC showed membrano-cytoplasmic expression (p = 0.011). The positive rate for synaptophysin was higher in MC type B and SPC than in MLL and MC type A (p = 0.001).
CONCLUSIONS
Similar MUC phenotypes were observed between MLL and MC type A and between MC type B and SPC.
Topics: Adenocarcinoma, Mucinous; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Immunohistochemistry; Mucin 5AC; Mucin-1; Mucin-2; Mucin-5B; Mucins
PubMed: 22269464
DOI: 10.1159/000334086 -
Current Opinion in Gastroenterology Jan 2024Gut microbiota-mucosa-epithelial cells co-exist in an intricate three-way relationship that underpins gut homeostasis, and ultimately influences health and disease... (Review)
Review
PURPOSE OF REVIEW
Gut microbiota-mucosa-epithelial cells co-exist in an intricate three-way relationship that underpins gut homeostasis, and ultimately influences health and disease conditions. The O-glycans of mucin glycoproteins have been uncovered as a centrepiece of this system, although understanding the phenomena at play at the molecular level has been challenging and subject to significant traction over the last years. The purpose of this review is to discuss the recent advances in the phenomena that mediate microbiota and mucus multidirectional interactions in the human gut.
RECENT FINDINGS
The mucus biosynthesis and degradation by both commensal and pathogenic bacteria is under tight regulation and involves hundreds of carbohydrate-active enzymes (CAZy) and transporters. The fucosylation of O-glycans from mucin-2 seems to dictate binding by pathogenic species and to influence their virulence. Less clear is the influence of O-glycans in quorum sensing and biofilm formation. We have reviewed the advances in the in vitro models available to recreate the phenomena that capture the physiological context of the intestinal environment, emphasising models that include mucus and other aspects relevant to the physiological context.
SUMMARY
The recent findings highlight the importance of merging advances in analytical (glycans analysis) and omics techniques along with original robust in vitro models that enable to deconstruct part of the high complexity of the living gut and expand our understanding of the microbes-mucosa relationships and their significance in health and disease.
Topics: Humans; Intestinal Mucosa; Mucins; Epithelial Cells; Polysaccharides; Bacteria
PubMed: 37983559
DOI: 10.1097/MOG.0000000000000992 -
World Journal of Gastroenterology Sep 2018To determine tissue expression (mRNA, protein) of two types of mucins [mucin 1 (MUC1) and mucin 2 (MUC2)] in patients with colorectal cancer (CRC). (Comparative Study)
Comparative Study
AIM
To determine tissue expression (mRNA, protein) of two types of mucins [mucin 1 (MUC1) and mucin 2 (MUC2)] in patients with colorectal cancer (CRC).
METHODS
Expression of membrane-bound mucin (MUC1) and secretory mucin (MUC2) in CRC (mRNA, protein) were analyzed in tissue material including fragments of tumors obtained from CRC patients ( = 34), and fragments of normal colorectal tissue from the same patients (control). The analysis was conducted using real-time quantitative polymerase chain reaction (RT-qPCR) (transcripts), immunohistochemistry (IHC) (apomucins), and the modern approach for morphometric analysis of IHC reaction (HSV filter software). Results on tissue expression of both mucins (mRNA, protein) were compared to histological alterations in colorectal cancer samples and correlated with selected clinical data in the patients. The statistical analysis was conducted using Statistica PL v. 12.0 software.
RESULTS
Significantly higher expression of the MUC1 mRNA in the CRC, compared with the control and the borderline correlation of mRNA expression with MUC1 protein levels in colorectal samples was observed. The expression of apomucins concerned cell membranes (MUC1) and cytoplasm (MUC2) and occurred both in control tissues and in most cancerous samples. There were no significant relationships between MUC1 (mRNA, protein) and the clinicopathological data of patients. MUC2 protein expression was significantly lower as compared to the control, while MUC2 mRNA expression was comparable in both groups. The MUC1/MUC2 ratio was significantly higher in CRC tissues than in the control. The higher expression of MUC2 was a feature of mucinous CRC subtypes, and characterized higher histological stage of tumors. Negative correlations have been obtained between MUC2 and the Ki-67 antigen, as well as between MUC2 and p53 protein expressions in CRC.
CONCLUSION
A combination of tissue overexpression of MUC1, reduced MUC2 expression, and high ratio of MUC1/MUC2 is a factor of poor prognosis in CRC patients. MUC2 tissue expression allows to differentiate mucinous and nonmucinous CRC subtypes.
Topics: Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Colorectal Neoplasms; Female; Humans; Intestine, Large; Male; Middle Aged; Mucin-1; Mucin-2; Neoplasm Staging; Prognosis; RNA, Messenger; Survival Rate
PubMed: 30271081
DOI: 10.3748/wjg.v24.i36.4164 -
British Medical Journal Sep 1951
Topics: Humans; Mucins
PubMed: 14869681
DOI: No ID Found -
Journal of Clinical Pathology Oct 1996
Topics: Adenocarcinoma; Coloring Agents; History, 17th Century; History, 18th Century; History, 19th Century; History, 20th Century; History, Ancient; Humans; Mucins; Staining and Labeling
PubMed: 8943740
DOI: 10.1136/jcp.49.10.787