Respiratory Distress and Neonatal Lethality in Mice Lacking Golgi α1,2-Mannosidase IB Involved in N-Glycan Maturation

Tremblay, Lucie; Kovács, Erzsébet Nagy; Daniels, Eugene; Wong, Nyet Kui; Sutton-Smith, Mark; Morris, Howard R.; Dell, Anne; Marcinkiewicz, Edwige; Seidah, Nabil G.; McKerlie, Colin; Herscovics, Annetté

doi:10.1074/jbc.m608661200

Cited by 22 publications

(18 citation statements)

References 46 publications

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“…Other steps in these pathways were accomplished by multiple enzyme isoforms (i.e. Golgi ␣-mannosidases (Man1a1, Man1a2, Man1c1), B3galT1-6, B4galt1-5), and transcript levels exhibited significant tissue-specific differences for many of the isoforms as previously indicated for these gene families (57)(58)(59)(60)(61)(62). Exceptions to this pattern include the single enzyme isoform, Mgat3, adding a bisecting ␤1,4-GlcNAc, and Fut8, adding a core ␣1,6-Fuc residue.…”

Section: Resultsmentioning

confidence: 58%

Regulation of Glycan Structures in Animal Tissues

Nairn

York

Harris

et al. 2008

Journal of Biological Chemistry

186

125

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Glycan structures covalently attached to proteins and lipids play numerous roles in mammalian cells, including protein folding, targeting, recognition, and adhesion at the molecular or cellular level. Regulating the abundance of glycan structures on cellular glycoproteins and glycolipids is a complex process that depends on numerous factors. Most models for glycan regulation hypothesize that transcriptional control of the enzymes involved in glycan synthesis, modification, and catabolism determines glycan abundance and diversity. However, few broad-based studies have examined correlations between glycan structures and transcripts encoding the relevant biosynthetic and catabolic enzymes. Low transcript abundance for many glycan-related genes has hampered broad-based transcript profiling for comparison with glycan structural data. In an effort to facilitate comparison with glycan structural data and to identify the molecular basis of alterations in glycan structures, we have developed a medium-throughput quantitative real time reverse transcriptase-PCR platform for the analysis of transcripts encoding glycan-related enzymes and proteins in mouse tissues and cells. The method employs a comprehensive list of >700 genes, including enzymes involved in sugar-nucleotide biosynthesis, transporters, glycan extension, modification, recognition, catabolism, and numerous glycosylated core proteins. Comparison with parallel microarray analyses indicates a significantly greater sensitivity and dynamic range for our quantitative real time reverse transcriptase-PCR approach, particularly for the numerous low abundance glycan-related enzymes. Mapping of the genes and transcript levels to their respective biosynthetic pathway steps allowed a comparison with glycan structural data and provides support for a model where many, but not all, changes in glycan abundance result from alterations in transcript expression of corresponding biosynthetic enzymes.Carbohydrate structures attached to glycoproteins, glycolipids, and proteoglycans have been shown to play key roles in a variety of biological recognition events (1). Although there are many examples of the contribution of N-glycans to the bioactivity, folding, localization, and immunogenicity of the attached polypeptide, the functional roles of individual oligosaccharide structures on a given glycoprotein are difficult to predict (1-5). At the cellular level, N-linked, O-linked, and glycolipid glycan structures have been shown to contribute to several essential aspects of biological recognition, including cell adhesion during development, immune surveillance, inflammatory reactions, hormone action, viral infection, arthritis, and metastasis of oncogenically transformed cells (6 -9). Most of our understanding of the roles of cellular glycosylation in physiology and pathology comes from a combination of glycan structural analysis on specific glycoproteins, cell surfaces, or total tissue extracts in combination with years of study on the biochemistry and enzymology of glycan biosynthetic...

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Section: Resultsmentioning

confidence: 58%

Regulation of Glycan Structures in Animal Tissues

Nairn

York

Harris

et al. 2008

Journal of Biological Chemistry

186

125

View full text Add to dashboard Cite

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“…In T cells, MAN2A1 and MAN2A2 are both expressed, and loss of the former is reported to have little effect on GlcNAc branching or T cell growth (21). Effects of targeted deletion of other Golgi ␣-mannosidase genes in T cells have not been explored (22,23). Here we report that TCR signaling enhances expression of all five Golgi ␣-mannosidase genes in parallel with Mgat5, an activity required for optimal production of ␤1,6GlcNAc-branched N-glycans.…”

mentioning

confidence: 80%

T Cell Receptor Signaling Co-regulates Multiple Golgi Genes to Enhance N-Glycan Branching

Chen

Grigorian

et al. 2009

Journal of Biological Chemistry

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T cell receptor (TCR) signaling enhances ␤1,6GlcNAc-branching in N-glycans, a phenotype that promotes growth arrest and inhibits autoimmunity by increasing surface retention of cytotoxic T lymphocyte antigen-4 (CTLA-4) via interactions with galectins. N-Acetylglucosaminyltransferase V (MGAT5) mediates ␤1,6GlcNAc-branching by transferring N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to N-glycan substrates produced by the sequential action of Golgi ␣1,2-mannosidase I (MIa,b,c), MGAT1, ␣1,2-mannosidase II (MII, IIx), and MGAT2. Here we report that TCR signaling enhances mRNA levels of MIa,b,c and MII,IIx in parallel with MGAT5, whereas limiting levels of MGAT1 and MGAT2. Blocking the increase in MI or MII enzyme activity induced by TCR signaling with deoxymannojirimycin or swainsonine, respectively, limits ␤1,6GlcNAc-branching, suggesting that enhanced MI and MII activity are both required for this phenotype. MGAT1 and MGAT2 have an ϳ250-and ϳ20-fold higher affinity for UDP-GlcNAc than MGAT5, respectively, and increasing MGAT1 expression paradoxically inhibits ␤1,6GlcNAc branching by limiting UDP-GlcNAc supply to MGAT5, suggesting that restricted changes in MGAT1 and MGAT2 mRNA levels in TCR-stimulated cells serves to enhance availability of UDP-GlcNAc to MGAT5. Together, these data suggest that TCR signaling differentially regulates multiple N-glycan-processing enzymes at the mRNA level to cooperatively promote ␤1,6GlcNAc branching, and by extension, CTLA-4 surface expression, T cell growth arrest, and self-tolerance.

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“…Inactive α1-4-mannosidase 1B disrupts pulmonary development (Tremblay, et al, 2007) Mouse (diabetic) human Liver…”

Section: Various Tissuesmentioning

confidence: 99%

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

Harvey

2011

Mass Spectrometry Reviews

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This review is the fifth update of the original review, published in 1999, on the application of MALDI mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2008. The first section of the review covers fundamental studies, fragmentation of carbohydrate ions, use of derivatives and new software developments for analysis of carbohydrate spectra. Among newer areas of method development are glycan arrays, MALDI imaging and the use of ion mobility spectrometry. The second section of the review discusses applications of MALDI MS to the analysis of different types of carbohydrate. Specific compound classes that are covered include carbohydrate polymers from plants, N- and O-linked glycans from glycoproteins, biopharmaceuticals, glycated proteins, glycolipids, glycosides and various other natural products. There is a short section on the use of MALDI mass spectrometry for the study of enzymes involved in glycan processing and a section on the use of MALDI MS to monitor products of the chemical synthesis of carbohydrates with emphasis on carbohydrate-protein complexes and glycodendrimers. Corresponding analyses by electrospray ionization now appear to outnumber those performed by MALDI and the amount of literature makes a comprehensive review on this technique impractical. However, most of the work relating to sample preparation and glycan synthesis is equally relevant to electrospray and, consequently, those proposing analyses by electrospray should also find material in this review of interest.

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Respiratory Distress and Neonatal Lethality in Mice Lacking Golgi α1,2-Mannosidase IB Involved in N-Glycan Maturation

Cited by 22 publications

References 46 publications

Regulation of Glycan Structures in Animal Tissues

Regulation of Glycan Structures in Animal Tissues

T Cell Receptor Signaling Co-regulates Multiple Golgi Genes to Enhance N-Glycan Branching

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

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