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Current Opinion in Structural Biology Apr 2023Contrary to first appearances, mucus structural biology is not an oxymoron. Though mucus hydrogels derive their characteristics largely from intrinsically disordered,... (Review)
Review
Contrary to first appearances, mucus structural biology is not an oxymoron. Though mucus hydrogels derive their characteristics largely from intrinsically disordered, heavily glycosylated polypeptide segments, the secreted mucin glycoproteins that constitute mucus undergo an orderly assembly process controlled by folded domains at their termini. Recent structural studies revealed how mucin complexes promote disulphide-mediated polymerization to produce the mucus gel scaffold. Additional protein-protein and protein-glycan interactions likely tune the mesoscale properties, stability, and activities of mucins. Evidence is emerging that even intrinsically disordered glycosylated segments have specific structural roles in the production and properties of mucus. Though soft-matter biophysical approaches to understanding mucus remain highly relevant, high-resolution structural studies of mucins and other mucus components are providing new perspectives on these vital, protective hydrogels.
Topics: Mucins; Mucus; Glycoproteins; Polysaccharides; Glycosylation
PubMed: 36753925
DOI: 10.1016/j.sbi.2022.102524 -
Nature Chemical Biology Jun 2023Mucinolytic bacteria modulate host-microbiota symbiosis and dysbiosis through their ability to degrade mucin O-glycans. However, how and to what extent bacterial enzymes...
Mucinolytic bacteria modulate host-microbiota symbiosis and dysbiosis through their ability to degrade mucin O-glycans. However, how and to what extent bacterial enzymes are involved in the breakdown process remains poorly understood. Here we focus on a glycoside hydrolase family 20 sulfoglycosidase (BbhII) from Bifidobacterium bifidum, which releases N-acetylglucosamine-6-sulfate from sulfated mucins. Glycomic analysis showed that, in addition to sulfatases, sulfoglycosidases are involved in mucin O-glycan breakdown in vivo and that the released N-acetylglucosamine-6-sulfate potentially affects gut microbial metabolism, both of which were also supported by a metagenomic data mining analysis. Enzymatic and structural analysis of BbhII reveals the architecture underlying its specificity and the presence of a GlcNAc-6S-specific carbohydrate-binding module (CBM) 32 with a distinct sugar recognition mode that B. bifidum takes advantage of to degrade mucin O-glycans. Comparative analysis of the genomes of prominent mucinolytic bacteria also highlights a CBM-dependent O-glycan breakdown strategy used by B. bifidum.
Topics: Mucins; Ecosystem; Polysaccharides; Bacteria
PubMed: 36864192
DOI: 10.1038/s41589-023-01272-y -
Journal of Clinical Pathology May 2004MUCs are glycoproteins with various roles in homeostasis and carcinogenesis. Among other actions, MUC1 may inhibit cell-cell and cell-stroma interactions and function as... (Review)
Review
MUCs are glycoproteins with various roles in homeostasis and carcinogenesis. Among other actions, MUC1 may inhibit cell-cell and cell-stroma interactions and function as a signal transducer, participating in cancer progression. In contrast, MUC2 is normally found only in goblet cells, where it contributes to the protective barrier function of these cells. Recently, a tumour suppressor role has been demonstrated for MUC2, and both MUC1 and MUC2 appear to have important roles in pancreatic neoplasia. MUC1 appears to be a marker of aggressive phenotype and may facilitate the vascular spread of carcinoma cells. In contrast, MUC2 is rarely detectable in aggressive pancreatic tumours, but is commonly expressed in intraductal papillary mucinous neoplasms (IPMNs), which are rare, indolent tumours, in intestinal IPMNs, and in indolent colloid carcinomas. MUC2 appears to be not only a marker of this indolent pathway, but also partly responsible for its less aggressive nature. Thus, in pancreatic neoplasia, MUC1 and MUC2 have potential diagnostic and prognostic value as markers of aggressive and indolent phenotypes, respectively, and have potential as therapeutic targets.
Topics: Cell Transformation, Neoplastic; Humans; Mucin-1; Mucin-2; Mucins; Neoplasm Invasiveness; Neoplasm Proteins; Pancreatic Neoplasms; Peptide Fragments
PubMed: 15113850
DOI: 10.1136/jcp.2003.013292 -
Digestive Diseases (Basel, Switzerland) 2021Mucus protects the epithelium against invaders and toxic materials. Sticky and thick mucus is characteristic of CF.
BACKGROUND
Mucus protects the epithelium against invaders and toxic materials. Sticky and thick mucus is characteristic of CF.
OBJECTIVE
The aim of this systematic review is to characterize the specific mucins secreted in the lung and intestinal tract of CF patients.
METHODS
A systematic literature search was conducted up to December 31, 2019. The following terms were used: "cystic fibrosis" AND "mucin." Case-control studies comparing mucin expression in CF patients to healthy controls were included.
RESULTS
We found 741 eligible studies, 694 studies were rejected because they were performed in animals and not in full text, and 32 studies were excluded being editorials, duplications, review articles, meta-analysis, or not in English. Fifteen studies were eligible for our study, including 150 CF patients compared to 82 healthy controls, all fulfilled the inclusion criteria. The main mucin types expressed in the sinus submucosal glands, sputum, tracheobronchial surface epithelium, and lung submucosal glands were MUC5AC and MUC5B. Increase in the number of sinusoidal submucosal glands and expression of MUC5B was found in CF patients, but no such difference from healthy controls was found for the number of goblet cells in the surface epithelium nor in the expression of -MUC5AC. The opposite was found in the tracheobronchial surface epithelium and in the lungs.
CONCLUSIONS
Increased expression of MUC5AC in the surface epithelium and of MUC5B in the subepithelial glands may be the result of higher secretion rate of mucin into the lumen of the respiratory tract, causing mucus plaque, infection, and inflammation.
Topics: Animals; Bodily Secretions; Case-Control Studies; Cystic Fibrosis; Gastrointestinal Tract; Humans; Lung; Mucin 5AC; Mucin-5B; Mucins
PubMed: 33049746
DOI: 10.1159/000512268 -
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 -
Biochemical Society Transactions Jun 2018In humans and mice, the first line of innate defense against inhaled pathogens and particles in the respiratory tract is airway mucus. The primary solid components of... (Review)
Review
In humans and mice, the first line of innate defense against inhaled pathogens and particles in the respiratory tract is airway mucus. The primary solid components of the mucus layer are the mucins MUC5AC and MUC5B, polymeric glycoproteins whose changes in abundance and structure can dramatically affect airway defense. Accordingly, and are tightly regulated at a transcriptional level by tissue-specific transcription factors in homeostasis and in response to injurious and inflammatory triggers. In addition to modulated levels of mucin gene transcription, translational and post-translational biosynthetic processes also exert significant influence upon mucin function. Mucins are massive macromolecules with numerous functional domains that contribute to their structural composition and biophysical properties. Single MUC5AC and MUC5B apoproteins have molecular masses of >400 kDa, and von Willebrand factor D-like as well as other cysteine-rich domain segments contribute to mucin polymerization and flexibility, thus increasing apoprotein length and complexity. Additional domains serve as sites for O-glycosylation, which increase further mucin mass several-fold. Glycosylation is a defining process for mucins that is specific with respect to additions of glycans to mucin apoprotein backbones, and glycan additions influence the physical properties of the mucins via structural modifications as well as charge interactions. Ultimately, through their tight regulation and complex assembly, airway mucins follow the biological rule of 'form fits function' in that their structural organization influences their role in lung homeostatic mechanisms.
Topics: Animals; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Lung; Mucins; Transcription, Genetic
PubMed: 29802217
DOI: 10.1042/BST20170455 -
Molecular Oncology Oct 2022Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the...
Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the mucinous subtype is known to elicit a worse response to chemotherapy and immunotherapy than the nonmucinous subtype, its pathogenesis remains poorly understood. Neurogenic locus notch homolog protein 3 (NOTCH3), a member of the NOTCH subfamilies, is highly expressed in CRC. In the past three decades, many studies have been performed evaluating the biological role of NOTCH3 in CRC. However, the precise activities of NOTCH3 in MCA, as well as the mechanisms involved in its transcriptional control, are yet to be elucidated. Our finding showed that the critical transcriptional regulatory factor transcription activator BRG1 (SMARCA4) directly binds to the intracellular domain of NOTCH3 to control transcriptional regulation. Moreover, RNA-sequencing results indicated a common targeting effect on the transcriptional activity of mucin-5AC (MUC5AC) and mucin-2 (MUC2) in CRC cells by NOTCH3 and SMARCA4. Furthermore, NOTCH3 was found to control the expressions of MUC5AC and MUC2 in a SMARCA4-dependent manner. MUC5AC and MUC2, which encode two secreted mucins, are located on chromosome 11p15.5, and are linked to the development of MCA. This finding suggests that the interaction between NOTCH3 and SMARCA4 may be involved in MCA differentiation by jointly targeting MUC5AC and MUC2. Patients with MCA are often treated in accordance with CRC guidelines. Determining the relationship between NOTCH3 and SMARCA4 by demonstrating their interactions in the pathophysiology of MCA could provide novel therapeutic targets and help identify potential prognostic markers for MCA.
Topics: Adenocarcinoma; Colorectal Neoplasms; DNA Helicases; Humans; Mucin 5AC; Mucin-2; Nuclear Proteins; RNA; Receptor, Notch3; Transcription Factors
PubMed: 35900231
DOI: 10.1002/1878-0261.13296 -
Cancer Letters Feb 2011Skin-related diseases comprise a major health challenge to the practicing physician, and constitute a significant psychological, social and financial burden to the... (Review)
Review
Skin-related diseases comprise a major health challenge to the practicing physician, and constitute a significant psychological, social and financial burden to the society. Further, skin cancer, especially non-melanoma skin cancer is currently the leading type of malignancy in the Western world. Given the huge burden of skin diseases, there is growing emphasis on understanding their pathophysiology, and towards their early detection. Mucins are high-molecular weight O- and N-linked glycoproteins that have emerged in recent years as important molecules in maintaining health and in promoting or protecting against inflammation and cancer. They have also begun to emerge as highly specific diagnostic and prognostic markers and novel therapeutic targets in several malignant disorders. However, their role in cutaneous pathologies has remained largely obscured. The present review provides the expression patterns and proposed role of mucins in the healthy skin and various benign and malignant skin diseases. The review has immense clinical significance as the availability of highly specific reagents including monoclonal antibodies against mucins makes them extremely attractive targets for specific diagnosis and/or immunotherapy of benign and malignant cutaneous diseases.
Topics: Animals; Biomarkers, Tumor; Humans; Models, Biological; Mucin 5AC; Mucin-1; Mucins; Multigene Family; Skin Neoplasms; Skin Physiological Phenomena
PubMed: 21146919
DOI: 10.1016/j.canlet.2010.11.004 -
Medecine Sciences : M/S Oct 2018Mucus is the first line of innate mucosal defense in all mammals. Gel‑forming mucins control the rheological properties of mucus hydrogels by forming a network in... (Review)
Review
Mucus is the first line of innate mucosal defense in all mammals. Gel‑forming mucins control the rheological properties of mucus hydrogels by forming a network in which hydrophilic and hydrophobic regions coexist, and it has been revealed that the network is formed through both covalent links and reversible links such as hydrophobic interactions in order to modulate the structure as a function of the physiological necessities. Here, we review the structure and functions of the mucus in terms of the gel-forming mucins protein-protein interactions, also called interactome. Since it is difficult to characterize the low energy reversible interactions due to their dependence on physico-chemical environment, their role is not well understood. Still, they constitute a promising target to counteract mucus abnormalities observed in mucus-associated diseases.
Topics: Animals; Elasticity; Gels; Humans; Mucins; Mucus; Rheology; Viscosity
PubMed: 30451674
DOI: 10.1051/medsci/2018206 -
Trends in Biochemical Sciences Apr 2010Mucins are high molecular weight glycoproteins that are involved in regulating diverse cellular activities both in normal and pathological conditions. Mucin activity and... (Review)
Review
Mucins are high molecular weight glycoproteins that are involved in regulating diverse cellular activities both in normal and pathological conditions. Mucin activity and localization is mediated by several molecular mechanisms, including discrete interactions with other proteins. An understanding of the biochemistry behind the known interactions between mucins and other proteins, coupled with an appreciation of their pathophysiological significance, can lend insight into the development of novel therapeutic agents. Indeed, a recent study demonstrated that a cell permeable inhibitor, PMIP, that disrupts the MUC1-EGFR interaction, is effective in killing breast cancer cells in vitro and in tumor models.
Topics: Humans; Mucins; Neoplasms; Protein Binding; Protein Structure, Tertiary; Transcription Factors; Wnt Proteins
PubMed: 19913432
DOI: 10.1016/j.tibs.2009.10.003