NEU1 Sialidase Regulates Membrane-tethered Mucin (MUC1) Ectodomain Adhesiveness for Pseudomonas aeruginosa and Decoy Receptor Release

Lillehoj, Erik P.; Hyun, Sang Won; Liu, Anguo; Guang, Wei; Verceles, Avelino C.; Luzina, Irina G.; Atamas, Sergei P.; Kim, K. Chul; Goldblum, Simeon E.

doi:10.1074/jbc.m115.657114

Cited by 33 publications

(100 citation statements)

References 45 publications

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“…Mucins and the monosaccharides that comprise O-linked glycans are conserved among many organisms. It had been previously reported that P. aeruginosa binding to human lung epithelial cells is reduced in the absence of specific mucins, namely, MUC1 (6,14,17,61). In addition, we have also demonstrated that monosaccharides reversed the binding defects observed in muc1-silenced cells, indicating that mucins may aid bacterial pathogenesis.…”

Section: Discussionsupporting

confidence: 73%

“…One of the low-affinity binding mechanisms used by microbes is mediated by hydrophobic interactions with lectins and glycosylated receptors, including oligosaccharides and monosaccharides present on mucins (4,(11)(12)(13). In addition to serving as a binding site, individual monosaccharides from mucins can be accessed as energy sources by bacteria with mucolytic activity (14). Finally, mucus components can influence the virulence characteristics of pathogenic bacteria, such as virulence factor expression, adhesion, motility, proliferation, and/or growth (3,7,8,(15)(16)(17)(18)(19).…”

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confidence: 99%

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Host Mucin Is Exploited by Pseudomonas aeruginosa To Provide Monosaccharides Required for a Successful Infection

Hoffman

Lalsiamthara

Aballay

2020

mBio

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One of the primary functions of the mucosal barrier, found lining epithelial cells, is to serve as a first-line of defense against microbial pathogens. The major structural components of mucus are heavily glycosylated proteins called mucins. Mucins are key components of the innate immune system as they aid in the clearance of pathogens and can decrease pathogen virulence. It has also been recently reported that individual mucins and derived glycans can attenuate the virulence of the human pathogen Pseudomonas aeruginosa. Here, we show data indicating that mucins not only play a role in host defense but that they can also be subverted by P. aeruginosa to cause disease. We found that the mucin MUL-1 and mucin-derived monosaccharides N-acetyl-galactosamine and N-acetylglucosamine are required for P. aeruginosa killing of Caenorhabditis elegans. We also found that the defective adhesion of P. aeruginosa to human lung alveolar epithelial cells, deficient in the mucin MUC1, can be reversed by the addition of individual monosaccharides. The monosaccharides identified in this study are found in a wide range of organisms where they act as host factors required for bacterial pathogenesis. While mucins in C. elegans lack sialic acid caps, which makes their monosaccharides readily available, they are capped in other species. Pathogens such as P. aeruginosa that lack sialidases may rely on enzymes from other bacteria to utilize mucin-derived monosaccharides. IMPORTANCE One of the first lines of defense present at mucosal epithelial tissues is mucus, which is a highly viscous material formed by mucin glycoproteins. Mucins serve various functions, but importantly they aid in the clearance of pathogens and debris from epithelial barriers and serve as innate immune factors. In this study, we describe a requirement of host monosaccharides, likely derived from host mucins, for the ability of Pseudomonas aeruginosa to colonize the intestine and ultimately cause death in Caenorhabditis elegans. We also demonstrate that monosaccharides alter the ability of bacteria to bind to both Caenorhabditis elegans intestinal cells and human lung alveolar epithelial cells, suggesting that there are conserved mechanisms underlying host-pathogen interactions in a range of organisms. By gaining a better understanding of pathogen-mucin interactions, we can develop better approaches to protect against pathogen infection.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

Host Mucin Is Exploited by Pseudomonas aeruginosa To Provide Monosaccharides Required for a Successful Infection

Hoffman

Lalsiamthara

Aballay

2020

mBio

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“…43 Given the normal clathrin-mediated endocytosis pathway utilized for recycling extracellular MUC1 (ref. 6) and that a major route of infection by IAV is via incorporation of the virion into the endosome after attachment to a Neu5Ac-containing receptor, we found it surprising that MUC1 did not facilitate IAV infection of host epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

The cell surface mucin MUC1 limits the severity of influenza A virus infection

et al. 2017

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Cell surface mucin (cs-mucin) glycoproteins are constitutively expressed at the surface of respiratory epithelia where pathogens such as influenza A virus (IAV) gain entry into cells. Different members of the cs-mucin family each express a large and heavily glycosylated extracellular domain that towers above other receptors on the epithelial cell surface, a transmembrane domain that enables shedding of the extracellular domain, and a cytoplasmic tail capable of triggering signaling cascades. We hypothesized that IAV can interact with the terminal sialic acids presented on the extracellular domain of cs-mucins, resulting in modulation of infection efficiency. Utilizing human lung epithelial cells, we found that IAV associates with the cs-mucin MUC1 but not MUC13 or MUC16. Overexpression of MUC1 by epithelial cells or the addition of sialylated synthetic MUC1 constructs, reduced IAV infection in vitro. In addition, Muc1 À / À mice infected with IAV exhibited enhanced morbidity and mortality, as well as greater inflammatory mediator responses compared to wild type mice. This study implicates the cs-mucin MUC1 as a critical and dynamic component of the innate host response that limits the severity of influenza and provides the foundation for exploration of MUC1 in resolving inflammatory disease.

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“…Bound bacteria were released with 0.05% trypsin, EDTA, and bound cfu were quantified on Luria-Bertani agar plates as described (60,61). Significance was determined by Student's t test.…”

Section: Methodsmentioning

confidence: 99%

“…Cell Adhesion-A549 human airway adenocarcinoma cells (52) (CCL 185, American Type Culture Collection (ATCC), Manassas, VA) or Detroit 562 pharyngeal carcinoma cells (53) (ATCC CCL 138) were seeded in 24-well culture plates and cultured at 37°C in 5% CO 2 to 2.0 ϫ 10 5 cells/well in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, 2.0 mM glutamine, 100 units/ml penicillin, and 100 g/ml streptomycin. The cells were washed twice with PBS, pH 7.2; fixed for 10 min at room temperature with 2.5% (v/v) glutaraldehyde in PBS, pH 7.2; and washed three times with PBS, pH 7.2 as described (60,61). A. nosocomialis M2 was cultured overnight in Luria-Bertani broth; washed twice with PBS, pH 7.2; resuspended in PBS, pH 7.2 containing 2.0 mg/ml glucose; and quantified spectrophotometrically at A 600 .…”

Section: Methodsmentioning

confidence: 99%

Structural Diversity in the Type IV Pili of Multidrug-resistant Acinetobacter

Piepenbrink

Lillehoj

Harding

et al. 2016

Journal of Biological Chemistry

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Acinetobacter baumannii is a Gram-negative coccobacillus found primarily in hospital settings that has recently emerged as a source of hospital-acquired infections. A. baumannii expresses a variety of virulence factors, including type IV pili, bacterial extracellular appendages often essential for attachment to host cells. Here, we report the high resolution structures of the major pilin subunit, PilA, from three Acinetobacter strains, demonstrating that A. baumannii subsets produce morphologically distinct type IV pilin glycoproteins. We examine the consequences of this heterogeneity for protein folding and assembly as well as host-cell adhesion by Acinetobacter. Comparisons of genomic and structural data with pilin proteins from other species of soil gammaproteobacteria suggest that these structural differences stem from evolutionary pressure that has resulted in three distinct classes of type IVa pilins, each found in multiple species.Type IV pili are extracellular adhesive appendages primarily comprising a single protein subunit, called the major pilin, which is assembled into a narrow (ϳ6 -9-nm) helical fiber of variable length (up to 2.5 m) (1). One or more other proteins, called minor pilins, are also incorporated into the fiber at low levels. All pilins contain an N-terminal signal sequence followed by an ϳ30-amino acid hydrophobic ␣-helix resembling a transmembrane domain (the ␣1-N domain). This is, in turn, followed by a soluble ϳ15-kDa globular domain referred to as the pilin headgroup; the hydrophobic helical regions are buried together in the center of the fiber, whereas portions of the C-terminal headgroup are exposed (2, 3).Type IV pili are found in both Gram-negative (4, 5) and Gram-positive (6 -8) bacteria as well as Archea (9). They are involved in a wide range of processes, including twitching motility (10), horizontal gene transfer (11), host-cell adhesion (12), and microcolony/biofilm formation (13). This functional diversity is reflected in the sequence of the pilin proteins that typically have little or no sequence identity beyond the hydrophobic portion of the N-terminal ␣-helix. This lack of sequence identity is apparent even in cases where there is high structural similarity.In contrast, within a given species, the minor pilins are typically well conserved. Only the major pilin is highly variable (14 -16) and then only in those regions left exposed in the assembled pilus (17). This sequence diversity may result from diversifying selection as a mechanism by which to avoid detection by the host immune system (18). However, such diversity can also be found in species whose life cycle is primarily environmental (19). Glycosylation is an additional source of variability in some type IV pilins; O-linked glycosylation has been observed in multiple strains of both Pseudomonas aeruginosa (20 -22) and Neisseria (23,24). Additional glycosylation sites have been found in class II strains of Neisseria meningitidis where they have been hypothesized to play a role in immune evasion (25).Among the man...

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NEU1 Sialidase Regulates Membrane-tethered Mucin (MUC1) Ectodomain Adhesiveness for Pseudomonas aeruginosa and Decoy Receptor Release

Cited by 33 publications

References 45 publications

Host Mucin Is Exploited by Pseudomonas aeruginosa To Provide Monosaccharides Required for a Successful Infection

Host Mucin Is Exploited by Pseudomonas aeruginosa To Provide Monosaccharides Required for a Successful Infection

The cell surface mucin MUC1 limits the severity of influenza A virus infection

Structural Diversity in the Type IV Pili of Multidrug-resistant Acinetobacter

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