Mucin gene structure and expression: protection vs. adhesion (original) (raw)
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Chapter 27. Epithelial mucins and bacterial adhesion
Carbohydrate Chemistry, 2014
Mucins are high molecular weight glycoproteins characterized by highly O-glycosylated tandem repeat domains. Mucin-type O-glycans exhibit a variety of terminal sequences including histo-blood group antigens that serve as counter receptors and participate in the adhesion and clearance of numerous bacteria including pathogens. In parallel, the pathological changes of mucin glycosylation modulate bacterial adhesion, often enhancing the adhesion of pathogenic bacteria. This review summarizes the current knowledge on the structure and biosynthesis of epithelial mucin O-glycans chains, the physio-pathological glycosylation repertoire of mucins and the role of mucin glycosylation in bacterial adhesion, focusing on the gastrointestinal tract and airway mucins.
Structure and function of epithelial mucins
Biopolymers and Cell, 1998
Mucins are the structural components of the epithelial mucose that protects the respiratory, gastrointestinal and reproductive tracts from the hostile environments, including microorganisms, toxim and abrasives. Mucins constitute a group of high molecular weight (> 200 kDa), polydisperse and highly glycosylated proteins which are present on the surface of most epithelial tissues. Our understanding of the structure and function of mucins has advanced significantly in the last decade. This progress was mainly associated with the isolation of the cDNA clones, encoding a family of epithelial mucins. To date, this family includes eight mucin genes (MUCJ-MUC8) and more await to be discovered. Based on sequence analysis and studies of subcellular localisation, epithelial mucins could be divided into two classes: membrane-associated (MUC1) and secretory (MUC2-8). This review is focused on our current knowledge of the structure of products of mucin genes and their function in normal tissues and in disease. The regulation of the expression of mucin genes, posttranslational modifications and alterations in secretion and processing will also be discussed.
The Polymorphic Epithelial Mucin as a Target for Immunotherapy
Annals of the New York Academy of Sciences, 1993
Mucins are large molecular weight glycoproteins that contain more than 50% carbohydrate linked to a core protein in 0-linkage to serines and threonines. The macrostructure of complex mucins, found in the gastrointestinal tract, lung, and ovary, has been studied for some time using physicochemical techniques, and some information regarding the structure of oligosaccharide side chains in some cases is available. However, only recently have structures of the much core proteins been elucidated, and this was made possible by recombinant DNA technology. The first gene to be isolated and sequenced was the MUCl gene coding for a highly polymorphic transmembrane molecule which we termed the polymorphic epithelial rnucin (PEM), but which was given a variety of names by other laboratories. The complete structure of the gene and its product is now known.'-6 An important motif in the core protein of PEM is a large domain in the extracellular portion of the molecule, which is made up of tandem repeats of 20 amino acids; variation in the number of these tandem repeats (30-100) is responsible for the polymorphism. Several other human mucin genes (MUC2-4, coding for mucins found in the lung and gastrointestinal as well as a porcine submaxillary mucin gene,'O genes coding for similar molecules in lower organisms,",'? and the mouse homolog of the human MUCl geneI3 were subsequently isolated. In each case, a large part of the mucin core protein was found to be made up of tandem repeats, which, although differing in length and sequence, in each case contained high levels of threonine, serine, and proline (TABLE 1). Although the complete structure of the core proteins of the complex gastrointestinal and lung mucins has not been elucidated, the available data suggest that they are probably not transmembrane molecules. Moreover, they contain cysteine-rich domain^'^.'^ that probably function to form covalently bonded aggregates. Such a structure was predicted from models arrived at from earlier studies of the effect of reducing agents on the molecular size of the complex, gel-forming mucins. Therefore, PEM may be unique among the mucins in that it lacks such cysteine-rich domains and is an intrinsic membrane glycoprotein. GLYCOSYLATION OF MUCINS In 0-linked glycosylation, the linkage sugar is N-acetylgalactosamine (GalNAc). The oligosaccharide side chain may then be extended with polylac-Lorna Stewart was supported by a Fellowship from Biomira Inc.
Molecular signaling in the regulation of mucins
Journal of Cellular Biochemistry, 2007
Mucins are large, highly glycosylated proteins involved in the protection of epithelia. The 20 different mucins show a diverse and highly regulated distribution among different epithelia. Most of the studies on mucin regulation done to date have been on the membrane mucins MUC1 and MUC4 and the gel-forming mucins. Multiple mechanisms have been implicated in that regulation, including examples at the transcriptional, transcript stabilization and posttranslational levels. Several signaling pathways have been demonstrated to be involved, most frequently the canonical Erk MAP kinase pathway, but also the cytokine-JAK-STAT pathway and TGFb-SMAD pathways. Diversity in Erk signaling is achieved through multiple activation mechanisms and multiple downstream transcriptional factors that are affected. Given the still limited amount of information available on regulation of most of the mucins, other mechanisms and pathways are likely to be uncovered in the future.
Glycoconjugate Journal, 2015
Mucins are major glycoprotein components of the mucus that coats the surfaces of cells lining the respiratory, digestive, gastrointestinal and urogenital tracts. They function to protect epithelial cells from infection, dehydration and physical or chemical injury, as well as to aid the passage of materials through a tract i.e., lubrication. They are also implicated in the pathogenesis of benign and malignant diseases of secretory epithelial cells. In Human there are two types of mucins, membrane-bound and secreted that are originated from mucous producing goblet cells localized in the epithelial cell layer or in mucous producing glands and encoded by MUC gene. Mucins belong to a heterogeneous family of high molecular weight proteins composed of a long peptidic chain with a large number of tandem repeats that form the so-called mucin domain. The molecular weight is generally high, ranging between 0.2 and 10 million Dalton and all mucins contain one or more domains which are highly glycosylated. The size and number of repeats vary between mucins and the genetic polymorphism represents number of repeats (VNTR polymorphisms), which means the size of individual mucins can differ substantially between individuals which can be used as markers. In human it is only MUC1 and MUC7 that have mucin domains with less than 40 % serine and threonine which in turn could reduce number of PTS domains. Mucins can be considered as powerful two-edged sword, as its normal function protects from unwanted substances and organisms at an arm's length while, malfunction of mucus may be an important factor in human diseases. In this review we have unearthed the current status of different mucin proteins in understanding its role and function in various noncommunicable diseases in human with special reference to its organ specific locations. The findings described in this review may be of direct relevance to the major research area in biomedicine with reference to mucin and mucin associated diseases.
MUC13, a Novel Human Cell Surface Mucin Expressed by Epithelial and Hemopoietic Cells
Journal of Biological Chemistry, 2001
Transmembrane mucins are glycoproteins involved in barrier function in epithelial tissues. To identify novel transmembrane mucin genes, we performed a tblastn search of the GenBank EST data bases with a serine/ threonine-rich search string, and a rodent gene expressed in bone marrow was identified. We determined the cDNA sequence of the human orthologue of this gene, MUC13, which localizes to chromosome band 3q13.3 and generates 3.2-kilobase pair transcripts encoding a 512-amino acid protein comprised of an N-terminal mucin repeat domain, three epidermal growth factor-like sequences, a SEA module, a transmembrane domain, and a cytoplasmic tail (GenBank accession no. AF286113). MUC13 mRNA is expressed most highly in the large intestine and trachea, and at moderate levels in the kidney, small intestine, appendix, and stomach. In situ hybridization in murine tissues revealed expression in intestinal epithelial and lymphoid cells. Immunohistochemistry demonstrated the human MUC13 protein on the apical membrane of both columnar and goblet cells in the gastrointestinal tract, as well as within goblet cell thecae, indicative of secretion in addition to presence on the cell surface. MUC13 is cleaved, and the -subunit containing the cytoplasmic tail undergoes homodimerization. Including MUC13, there are at least five cell surface mucins expressed in the gastrointestinal tract.
Expression of conserved mucin domains by epithelial tissues in various mammalian species
Research in Veterinary Science, 2009
Mucins are related to infectious and non-infectious diseases in Veterinary and Human Medicine. MUC1 mucin is a transmembrane glycoprotein expressed on the apical surface of human epithelia while MUC5AC is the predominant secreted mucin expressed in human gastric epithelium and goblet cells of lung and eyes. MUC5AC C-terminus cysteine rich regions and the cytoplasmic tail of MUC1 domains are conserved among several mammalian species. Objective: to compare the expression of MUC1 and MUC5AC mucins in mammalian epithelia. CT33 anti-MUC1 cytoplasmic tail (MUC1CT) polyclonal antibody and 45M1 anti-MUC5AC monoclonal antibody were employed. By immunohistochemistry, MUC1CT was expressed in most tissues while MUC5AC was restricted to gastric surface epithelium and goblet cells from trachea and lung. By western blot, MUC1CT showed a band at approximately 35 kDa in most tissues; MUC5AC revealed bands at >180 kDa in stomach and lung secretions from rat, cat, pig and cow. When rat MUC5AC was immunoprecipitated, a band at about 180 kDa was obtained.
MUC1 cell surface mucin is a critical element of the mucosal barrier to infection
Journal of Clinical Investigation, 2007
Cell surface mucin glycoproteins are highly expressed by all mucosal tissues, yet their physiological role is currently unknown. We hypothesized that cell surface mucins protect mucosal cells from infection. A rapid progressive increase in gastrointestinal expression of mucin 1 (Muc1) cell surface mucin followed infection of mice with the bacterial pathogen Campylobacter jejuni. In the first week following oral infection, C. jejuni was detected in the systemic organs of the vast majority of Muc1(-/-) mice but never in Muc1(+/+) mice. Although C. jejuni entered gastrointestinal epithelial cells of both Muc1(-/-) and Muc1(+/+) mice, small intestinal damage as manifested by increased apoptosis and enucleated and shed villous epithelium was more common in Muc1(-/-) mice. Using radiation chimeras, we determined that prevention of systemic infection in wild-type mice was due exclusively to epithelial Muc1 rather than Muc1 on hematopoietic cells. Expression of MUC1-enhanced resistance to C. jejuni cytolethal distending toxin (CDT) in vitro and CDT null C. jejuni showed lower gastric colonization in Muc1(-/-) mice in vivo. We believe this is the first in vivo experimental study to demonstrate that cell surface mucins are a critical component of mucosal defence and that the study provides the foundation for exploration of their contribution to epithelial infectious and inflammatory diseases.