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6. N-Glycan on the Non-Consensus N-X-C Glycosylation Site Impacts Activity, Stability, and Localization of the Sda Synthase B4GALNT2

Author

Cogez, Virginie, primary, Vicogne, Dorothée, additional, Schulz, Céline, additional, Portier, Lucie, additional, Venturi, Giulia, additional, de Ruyck, Jérôme, additional, Decloquement, Mathieu, additional, Lensink, Marc F., additional, Brysbaert, Guillaume, additional, Dall’Olio, Fabio, additional, Groux-Degroote, Sophie, additional, and Harduin-Lepers, Anne, additional

Published
2023
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11. N -Glycan on the Non-Consensus N-X-C Glycosylation Site Impacts Activity, Stability, and Localization of the Sd a Synthase B4GALNT2.

Author

Cogez, Virginie, Vicogne, Dorothée, Schulz, Céline, Portier, Lucie, Venturi, Giulia, de Ruyck, Jérôme, Decloquement, Mathieu, Lensink, Marc F., Brysbaert, Guillaume, Dall'Olio, Fabio, Groux-Degroote, Sophie, and Harduin-Lepers, Anne

Subjects
GLYCOSYLATION, GENE expression, SITE-specific mutagenesis, COLON cancer, ENDOPLASMIC reticulum, GLYCANS
Abstract

The Sda carbohydrate epitope and its biosynthetic B4GALNT2 enzyme are expressed in the healthy colon and down-regulated to variable extents in colon cancer. The human B4GALNT2 gene drives the expression of a long and a short protein isoform (LF-B4GALNT2 and SF-B4GALNT2) sharing identical transmembrane and luminal domains. Both isoforms are trans-Golgi proteins and the LF-B4GALNT2 also localizes to post-Golgi vesicles thanks to its extended cytoplasmic tail. Control mechanisms underpinning Sda and B4GALNT2 expression in the gastrointestinal tract are complex and not fully understood. This study reveals the existence of two unusual N-glycosylation sites in B4GALNT2 luminal domain. The first atypical N-X-C site is evolutionarily conserved and occupied by a complex-type N-glycan. We explored the influence of this N-glycan using site-directed mutagenesis and showed that each mutant had a slightly decreased expression level, impaired stability, and reduced enzyme activity. Furthermore, we observed that the mutant SF-B4GALNT2 was partially mislocalized in the endoplasmic reticulum, whereas the mutant LF-B4GALNT2 was still localized in the Golgi and post-Golgi vesicles. Lastly, we showed that the formation of homodimers was drastically impaired in the two mutated isoforms. An AlphaFold2 model of the LF-B4GALNT2 dimer with an N-glycan on each monomer corroborated these findings and suggested that N-glycosylation of each B4GALNT2 isoform controlled their biological activity. [ABSTRACT FROM AUTHOR]

Published
2023
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12. The story of the Sda antigen and of its cognate enzyme B4GALNT2: What is new?

Author

Duca, Martina, Malagolini, Nadia, and Dall'Olio, Fabio

Abstract

The structure Siaα2,3(GalNAcβ1,4)Gal- is the epitope of the Sda antigen, which is expressed on the erythrocytes and secretions of the vast majority of Caucasians, carried by N- and O-linked chains of glycoproteins, as well as by glycolipids. Sda is very similar, but not identical, to ganglioside GM2 [Siaα2,3(GalNAcβ1,4)Galβ1,4Glc-Cer]. The Sda synthase β1,4 N-acetylgalactosaminyl transferase 2 (B4GALNT2) exists in a short and a long form, diverging in the aminoterminal domain. The latter has a very long cytoplasmic tail and displays a Golgi- as well as a post-Golgi localization. The biosynthesis of Sda is mutually exclusive with that of the cancer-associated sialyl Lewis antigens, whose structure is Siaα2,3Galβ1,3/4(Fucα1,4/3)GlcNAc-. B4GALNT2 is down-regulated in colon cancer but patients with higher expression survive longer. In experimental systems, B4GALNT2 inhibits colon cancer progression,not only through inhibition of sialyl Lewis antigen biosynthesis. By contrast, in breast cancer B4GALNT2 is associated with malignancy. In colon cancer, the B4GALNT2 gene is regulated by multiple mechanisms, which include miRNA and transcription factor expression, as well as CpG methylation. In addition, Sda/B4GALNT2 regulates the susceptibility to infectious agents, the protection from muscle dystrophy, the activity of immune system in pregnancy and the immune rejection in xenotransplantation. [ABSTRACT FROM AUTHOR]

Published
2023
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16. Impact of Glycosyltransferases on the Phenotype, Signaling and Transcriptome of Colorectal Cancer Cell Lines. Focus on the role of glycosyltransferases B4GALNT2 and FUT6 and their cognate Sda and sLex antigens

Author

Dall'olio, Fabio, Pucci, Michela <1991>, Dall'olio, Fabio, and Pucci, Michela <1991>

Abstract

In colorectal cancer (CRC), two carbohydrate structures are modulated: the Sda antigen, synthesized by B4GALNT2, and sLex antigen, mainly synthesized by FUT6. sLex antigen is often overexpressed and associated with worse prognosis; B4GALNT2/Sda antigen are dramatically downregulated but their role in tumor progression and development is not fully clear. TCGA interrogation revealed a dramatic down-regulation of B4GALNT2 mRNA in CRC, compared with normal samples. Patients with higher B4GALNT2 mRNA in CRC samples displayed longer survival. Yet, methylation and miRNA expression play a relevant role in B4GALNT2 downregulation in CRC. To clarify the mechanisms linking the B4GALNT2/Sda expression level to CRC phenotype, three different CRC cell lines were modified to express B4GALNT2: LS174T cell line, in which the constitutively expressed sLex antigen was partially replaced by Sda; SW480/SW620 pair, both lacking Sda and sLex antigens. In LS174T cells, the expression of B4GALNT2 reduced the ability to grow in poor adherence conditions and the expression of ALDH, a stemness marker. In SW620 cells, B4GALNT2 expression impacted on the main aspects of malignancy. In SW480 cells the expression of B4GALNT2 left unchanged the proliferation rate and the wound healing ability. To clarify the impact of sLex on CRC phenotype, the SW480/SW620 pair were permanently transfected to express FUT6 cDNA. In both cell lines, overexpression of FUT6/sLex boosted the clonogenic ability in standard growth conditions. Conversely, the growth in soft agar and the capacity to close a wound were enhanced only in SW620 cells. Transcriptome analysis of CRC cell lines transfected either with B4GALNT2 or FUT6 showed a relevant impact of both enzymes on gene expression modulation. Overall, current data may help to personalize therapies for CRC patients according to the B4GALNT2 levels and support a causal effect of this glycosyltransferase on reducing malignancy independently of sLex inhibition.

Published
2021

20. Bladder cancer–glycosylation insights

Author

Severino, Paulo F., primary, Silva, Mariana, additional, Carrascal, Mylène A., additional, Calais, Fernando, additional, Dall’Olio, Fabio, additional, and Videira, Paula A., additional

Published
2012
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23. L1CAM as an E-selectin Ligand in Colon Cancer

Author

Deschepper, Fanny M., primary, Zoppi, Roberta, additional, Pirro, Martina, additional, Hensbergen, Paul J., additional, Dall’Olio, Fabio, additional, Kotsias, Maximillianos, additional, Gardner, Richard A., additional, Spencer, Daniel I.R., additional, and Videira, Paula A., additional

Published
2020
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27. Fetal bovine serum impacts the observed N‐glycosylation defects in TMEM165 KO HEK cells

Author

Climer, Leslie, Morelle, Willy, De Bettignies, Geoffroy, Krzewinski Recchi, Marie-Ange, Lupashin, Vladimir, Medina-Cano, Daniel, Ucuncu, Ekin, Nguyen, Lam Son, Nicouleau, Michael, Lipecka, Joanna, Bizot, Jean-Charles, Thiel, Christian, Lefort, Nathalie, Faivre-Sarrailh, Catherine, Colleaux, Laurence, Guerrera, Ida Chiara, Cantagrel, Vincent, Lebredonchel, Elodie, Garat, Anne, Legrand, Dominique, Decool, Valérie, Klein, André, Ouzzine, Mohamed, Gasnier, Bruno, Potelle, Sven, Groux‐Degroote, Sophie, Cogez, Virginie, Noel, Maxence, Portier, Lucie, Solórzano, Carlos, Dall'Olio, Fabio, Steenackers, Agata, Mortuaire, Marlène, Gonzalez‐Pisfil, Mariano, Henry, Mélanie, Heliot, Laurent, Harduin-Lepers, Anne, Berthe, Audrey, Zaffino, Marie, Muller, claire, Houdou, Marine, Schulz, Céline, Bost, Frédéric, De Fay, Elia, Mazerbourg, Sabine, Flament, Stéphane, Mouajjah, Dounia, Ashikov, Angel, Abu Bakar, Nurulamin, Wen, Xiao-Yan, Niemeijer, Marco, Rodrigues Pinto Osorio, Glentino, Brand-Arzamendi, Koroboshka, Hasadsri, Linda, Hansikova, Hana, Raymond, Kimiyo, Ondruskova, Nina, Simon, Marleen, Pfundt, Rolph, Timal, Sharita, Beumers, Roel, Smeets, Roel, Kersten, Marjan, Huijben, Karin, Linders, Peter, van den Bogaart, Geert, van Hijum, Sacha, Rodenburg, Richard, van den Heuvel, Lambertus, Van Spronsen, Francjan, Honzik, Tomas, van Scherpenzeel, Monique, Lefeber, Dirk, Mirjam, Wamelink, Han, Brunner, Helen, Mundy, Helen, Michelakakis, Peter, van Hasselt, Jiddeke, van de Kamp, Diego, Martinelli, Lars, Morkrid, Katja, Brocke Holmefjord, Jozef, Hertecant, Majid, Alfadhel, Kevin, Carpenter, Johann, te Water Naude, Delos, Maxime, Hellec, Charles, Fifre, Alexandre, Carpentier, Mathieu, Papy-Garcia, Dulce, Allain, Fabrice, Denys, Agnés, Gilormini, Pierre André, Lion, Cédric, Vicogne, Dorothée, Guerardel, Yann, Biot, Christophe, Witters, Peter, Breckpot, Jeroen, Preston, Graem, Morava, Eva, Rujano, Maria, Cannata Serio, Magda, Panasyuk, Ganna, Reunert, Janine, Hauser, Virginie, Park, Julien, Freisinger, Peter, Guida, Maria Clara, Maier, Esther, Wada, Yoshinao, Jäger, Stefanie, Krogan, Nevan, Kretz, Oliver, Nobre, Susana, Garcia, Paula, Quelhas, Dulce, Bird, Thomas, Raskind, Wendy, Schwake, Michael, Duvet, Sandrine, Marquardt, Thorsten, Simons, Matias, Blommaert, Eline, Péanne, Romain, Cherepanova, Natalia, Rymen, Daisy, Staels, Frederik, Jaeken, Jaak, Race, Valérie, Keldermans, Liesbeth, Souche, Erika, Corveleyn, Anniek, Sparkes, Rebecca, Bhattacharya, Kaustuv, Devalck, Christine, Schrijvers, Rik, Foulquier, Francois, Gilmore, Reid, Matthijs, Gert, Université Lille Nord de France (COMUE), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Variabilité génétique des défenses de l'organisme face à son environnement chimique, PRES Université Lille Nord de France-Université de Lille, Droit et Santé, ANR-15-CE14-0001,SOLV_CDG,Décryptage des patients CDG (Congenital Disorders of Glyvosylation) déficients en TMEM165 - de la compréhension des mécanismes moléculaires à une thérapie(2015), ANR-15-RAR3-0004,EURO-CDG-2,A European research network directed towards improving diagnosis and treatment of inborn glycosylation disorders.(2015), European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS], Baylor University, University of Arkansas for Medical Sciences [UAMS], Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Key-Obs, JRC Institute for Energy and Transport (IET), European Commission - Joint Research Centre [Petten], Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Impact de l'environnement chimique sur la santé humaine (IMPECS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Biologie cellulaire et moléculaire de la sécrétion (BCMS), Centre National de la Recherche Scientifique (CNRS), Departamento de Bioquímica, Instituto Nacional de Enfermedades Respiratorias, Department of Experimental, Diagnostic and Specialty Medicine (DIMES) (DIMES), Università di Bologna [Bologna] (UNIBO), Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 (PhLAM), Biophotonique Cellulaire Fonctionelle, Institut de Recherche Interdisciplinaire, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] (IRI), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine & Physiology , University of Toronto, First Faculty of Medicine, Charles University [Prague], University Medical Center [Utrecht], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Paediatrics, Beatrix Children's Hospital/University Medical Center Groningen, Université Toulouse 1 Capitole (UT1), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Chimie Moléculaire et Formulation (EA 4478), Université de Lille, Sciences et Technologies, Unité de Catalyse et de Chimie du Solide - UMR 8181 (UCCS), Université d'Artois (UA)-Ecole Centrale de Lille-Ecole Nationale Supérieure de Chimie de Lille (ENSCL)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University Children's Hospital, Centre de recherche Croissance et signalisation (UMR_S 845), Reutlingen University, Department of General Pediatrics, Münster University Children Hospital, Molecular Diagnostics, Center for Human Genetics, Gasthuisberg, Katholieke Universiteit Leuven and Flanders Interuniversity Institute for Biotechnology 4, Leuven, Belgium, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Center for Human Genetics, and Laboratory of clinical immunology

Subjects
Glycosylation, Protein family, [SDV]Life Sciences [q-bio], Golgi Apparatus, FBS, manganese level, N‐glycosylation defects, TMEM165, Article, Antiporters, Glycomics, 03 medical and health sciences, chemistry.chemical_compound, symbols.namesake, Congenital Disorders of Glycosylation, 0302 clinical medicine, N-linked glycosylation, Genetics, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cation Transport Proteins, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Manganese, 0303 health sciences, Ion Transport, HEK 293 cells, Serum Albumin, Bovine, Golgi apparatus, Embryonic stem cell, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], carbohydrates (lipids), HEK293 Cells, chemistry, symbols, Calcium, 030217 neurology & neurosurgery, Fetal bovine serum
Abstract

TMEM165 is involved in a rare genetic human disease named TMEM165‐CDG (congenital disorders of glycosylation). It is Golgi localized, highly conserved through evolution and belongs to the uncharacterized protein family 0016 (UPF0016). The use of isogenic TMEM165 KO HEK cells was crucial in deciphering the function of TMEM165 in Golgi manganese homeostasis. Manganese is a major cofactor of many glycosylation enzymes. Severe Golgi glycosylation defects are observed in TMEM165 Knock Out Human Embryonic Kidney (KO HEK) cells and are rescued by exogenous manganese supplementation. Intriguingly, we demonstrate in this study that the observed Golgi glycosylation defect mainly depends on fetal bovine serum, particularly its manganese level. Our results also demonstrate that iron and/or galactose can modulate the observed glycosylation defects in TMEM165 KO HEK cells. While isogenic cultured cells are widely used to study the impact of gene defects on proteins' glycosylation patterns, these results emphasize the importance of the use of validated fetal bovine serum in glycomics studies. 43;2

Published
2019

30. Functional relationship of colorectal cancer-associated glycans with malignant phenotype and transcriptome changes

Author

Dall'olio, Fabio, Gomes Ferreira, Ines Isabel <1992>, Dall'olio, Fabio, and Gomes Ferreira, Ines Isabel <1992>

Abstract

Glycosyltransferases ST6GAL1 and B4GALNT2 (and their cognate antigens Sia6LacNAc and Sda, respectively) are associated with colorectal cancer (CRC) but it is not fully clear their biological and clinical significance. We explored the clinical relevance of both glycosyltransferases by interrogating The Cancer Genome Atlas (TCGA) database while the phenotypic/transcriptomic effects of ST6GAL1/B4GALNT2 overexpression were studied in genetically modified CRC cell lines. Transcriptomic data from CRC patients in TCGA database suggested a moderate impact of ST6GAL1 on CRC progression, although it was not possible to define a clear role for this glycosyltransferase. Transcriptomic analysis of ST6GAL1-transduced cell lines revealed a much deeper effect of ST6GAL1 on gene expression in SW948 than in SW48. The overexpression of ST6GAL1 induced opposite effects on soft agar growth and wound healing in both cell lines. These results indicate that the impact of a cancer-associated glycosyltransferase change on phenotype/transcriptome can be extremely variable, depending on the molecular context of the tumor cell. On the contrary, transcriptomic analysis of B4GALNT2-modified cell lines together with TCGA database survey demonstrated a strong impact of B4GALNT2 on the transcriptional activity of CRC cells, in particular its association with a better prognosis. We suggest an anti-tumoral role of B4GALNT2 in CRC. We also investigated the glycan changes related to ST6GAL1/B4GALNT2 expression in a small cohort of tissues/plasma as well as the N-glycomic profile of CRC, normal and polyp tissues. We found an increase of ST6GAL1 activity in CRC and inflammatory bowel disease plasma samples comparing with plasma from healthy donors. A different Sda protein carrier pattern was observed between healthy donors and CRC plasma samples. β-arrestin 1 is a possible candidate as Sda carrier protein in plasma samples although future validation studies are needed. The alterations found in the N-glyca

Published
2019

34. The extended cytoplasmic tail of the human B4GALNT2 is critical for its Golgi targeting and post-Golgi sorting

Author

Harduin-Lepers, Anne, Groux-Degroote, Sophie, Schulz, Céline, Cogez, Virginie, Noel, Maxence, Portier, Lucie, Vicogne, Dorothée, Solórzano, Carlos, Dall'Olio, Fabio, Steenackers, Agata, Mortuaire, Marlène, Gonzalez-Pisfil, Mariano, Henry, Mélanie, Foulquier, Francois, Héliot, Laurent, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] (IRI), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Departamento de Bioquímica, Instituto Nacional de Enfermedades Respiratorias, Department of Experimental, Diagnostic and Specialty Medicine (DIMES) (DIMES), Università di Bologna [Bologna] (UNIBO), Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 (PhLAM), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé-Université de Lille, Sciences et Technologies

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract

International audience

Published
2018

38. Total loss of GM3 synthase activity by a normally processed enzyme in a novel variant and in all ST3GAL5 variants reported to cause a distinct congenital disorder of glycosylation

Author

Indellicato, Rossella, primary, Parini, Rossella, additional, Domenighini, Ruben, additional, Malagolini, Nadia, additional, Iascone, Maria, additional, Gasperini, Serena, additional, Masera, Nicoletta, additional, dall’Olio, Fabio, additional, and Trinchera, Marco, additional

Published
2019
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39. ST3Gal.I sialyltransferase relevance in bladder cancer tissues and cell lines

Author

Calais Fernando M, Ligeiro Dário, Crespo Hélio J, Malagolini Nadia, Correia Manuela, Videira Paula A, Trindade Helder, and Dall'Olio Fabio

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The T antigen is a tumor-associated structure whose sialylated form (the sialyl-T antigen) involves the altered expression of sialyltransferases and has been related with worse prognosis. Since little or no information is available on this subject, we investigated the regulation of the sialyltransferases, able to sialylate the T antigen, in bladder cancer progression. Methods Matched samples of urothelium and tumor tissue, and four bladder cancer cell lines were screened for: ST3Gal.I, ST3Gal.II and ST3Gal.IV mRNA level by real-time PCR. Sialyl-T antigen was detected by dot blot and flow cytometry using peanut lectin. Sialyltransferase activity was measured against the T antigen in the cell lines. Results In nonmuscle-invasive bladder cancers, ST3Gal.I mRNA levels were significantly higher than corresponding urothelium (p < 0.001) and this increase was twice more pronounced in cancers with tendency for recurrence. In muscle-invasive cancers and matching urothelium, ST3Gal.I mRNA levels were as elevated as nonmuscle-invasive cancers. Both non-malignant bladder tumors and corresponding urothelium showed ST3Gal.I mRNA levels lower than all the other specimen groups. A good correlation was observed in bladder cancer cell lines between the ST3Gal.I mRNA level, the ST activity (r = 0.99; p = 0.001) and sialyl-T antigen expression, demonstrating that sialylation of T antigen is attributable to ST3Gal.I. The expression of sialyl-T antigens was found in patients' bladder tumors and urothelium, although without a marked relationship with mRNA level. The two ST3Gal.I transcript variants were also equally expressed, independently of cell phenotype or malignancy. Conclusion ST3Gal.I plays the major role in the sialylation of the T antigen in bladder cancer. The overexpression of ST3Gal.I seems to be part of the initial oncogenic transformation of bladder and can be considered when predicting cancer progression and recurrence.

Published
2009
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40. The impact of ST6Gal-I in the progression of colorectal cancer

Author

Dall'Olio, Fabio, Venturi, Giulia <1989>, Dall'Olio, Fabio, and Venturi, Giulia <1989>

Abstract

One of the hallmarks associated with cancer is an aberrant expression of glycans decorating the plasma membrane due to altered expression of glycosyltransferases. The elevation of sialyltransferase ST6Gal-I and of its cognate glycan structure Sia6LacNAc has been described in colon and other cancers and controversially associated with malignancy. In this study, we investigated the relationship between ST6Gal-I mRNA expression and clinical features in a cohort of over 600 colorectal cancer (CRC) cases on The Cancer Genome Atlas, finding that low ST6Gal-I expression was associated with a microsatellite unstable and mucinous phenotype, and with BRAF mutation, but not with clinical stage or survival. To investigate the effect of ST6Gal-I overexpression on CRC, we retrovirally transduced with the human ST6Gal-I cDNA or with an empty vector the cell lines SW48 (microsatellite unstable) and SW948 (chromosomal unstable), generating their ST and NC variants respectively. Transcriptomic analysis of the two cell lines revealed a higher number of modulated genes in SW948 ST compared with SW48 ST. SW948 ST (but not SW48 ST) displayed an accelerated apoptotic response compared to NC, while SW948 ST (but not SW48 ST) displayed increased ability to heal the wound than SW948 NC. In soft agar assay, SW948 ST (but not SW48 ST) cells generated fewer clones, although bigger, than SW948 NC. SW48 ST (but not SW948 ST) displayed a reduced capacity to invade Matrigel compared to NC. Treatment with HGF caused an increase of FAK phosphorylation in SW948 NC cells and a decrease in ST cells. Similar results were observed in SW48 NC and ST cells. With ALDH staining we observed a population of cancer stem cells in the two cell lines with no differences derived from ST6Gal-I overexpression. These results indicate a very cell type specific effect of ST6GAL1 and Sia6LacNAc on the phenotype of CRC cells.

Published
2018

41. A novel nonsense and inactivating variant of ST3GAL3 in two infant siblings suffering severe epilepsy and expressing circulating CA19.9.

Author

Indellicato, Rossella, Domenighini, Ruben, Malagolini, Nadia, Cereda, Anna, Mamoli, Daniela, Pezzani, Lidia, Iascone, Maria, dall'Olio, Fabio, and Trinchera, Marco

Subjects
GOLGI apparatus, CONGENITAL disorders, SIBLINGS, INFANTS, EPILEPSY, CONFOCAL microscopy, GLYCANS, CEFEPIME
Abstract

Three missense variants of ST3GAL3 are known to be responsible for a congenital disorder of glycosylation determining a neurodevelopmental disorder (intellectual disability/epileptic encephalopathy). Here we report a novel nonsense variant, p.Y220*, in two dichorionic infant twins presenting a picture of epileptic encephalopathy with impaired neuromotor development. Upon expression in HEK-293T cells, the variant appears totally devoid of enzymatic activity in vitro, apparently accumulated with respect to the wild-type or the missense variants, as detected by western blot, and in large part properly localized in the Golgi apparatus, as assessed by confocal microscopy. Both patients were found to efficiently express the CA19.9 antigen in the serum despite the total loss of ST3GAL3 activity, which thus appears replaceable from other ST3GALs in the synthesis of the sialyl-Lewis a epitope. Kinetic studies of ST3GAL3 revealed a strong preference for lactotetraosylceramide as acceptor and gangliotetraosylceramide was also efficiently utilized in vitro. Moreover, the p.A13D missense variant, the one maintaining residual sialyltransferase activity, was found to have much lower affinity for all suitable substrates than the wild-type enzyme with an overall catalytic efficiency almost negligible. Altogether the present data suggest that the apparent redundancy of ST3GALs deduced from knock-out mouse models only partially exists in humans. In fact, our patients lacking ST3GAL3 activity synthesize the CA19.9 epitope sialyl-Lewis a, but not all glycans necessary for fine brain functions, where the role of minor gangliosides deserves further attention. [ABSTRACT FROM AUTHOR]

Published
2020
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42. The extended cytoplasmic tail of the human B4GALNT2 is critical for its Golgi targeting and post‐Golgi sorting

Author

Groux‐Degroote, Sophie, primary, Schulz, Céline, additional, Cogez, Virginie, additional, Noël, Maxence, additional, Portier, Lucie, additional, Vicogne, Dorothée, additional, Solorzano, Carlos, additional, Dall'Olio, Fabio, additional, Steenackers, Agata, additional, Mortuaire, Marlène, additional, Gonzalez‐Pisfil, Mariano, additional, Henry, Mélanie, additional, Foulquier, François, additional, Héliot, Laurent, additional, and Harduin‐Lepers, Anne, additional

Published
2018
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46. Expression of sialyl-Tn sugar antigen in bladder cancer cells affects response to Bacillus Calmette Guérin (BCG) and to oxidative damage

Author

Severino, Paulo F., primary, Silva, Mariana, additional, Carrascal, Mylene, additional, Malagolini, Nadia, additional, Chiricolo, Mariella, additional, Venturi, Giulia, additional, Astolfi, Annalisa, additional, Catera, Mariangela, additional, Videira, Paula A., additional, and Dall’Olio, Fabio, additional

Published
2017
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48. The expanding roles of the Sda/Cad carbohydrate antigen and its cognate glycosyltransferase B4GALNT2

Author

Dall'Olio, Fabio, Malagolini, Nadia, Chiricolo, Mariella, Trinchera, Marco, Harduin-Lepers, Anne, Harduin- Lepers, Anne, Department of Experimental, Diagnostic and Specialty Medicine (DIMES) (DIMES), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Medicine Clinical and Experimental (DMCS), Universitá degli Studi dell’Insubria, Université Lille Nord de France (COMUE), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Université de Lille-Centre National de la Recherche Scientifique (CNRS), CNRS, Université Lille Nord de France, Lille1, Arcir 'dynamique' Région Nord-Pas de Calais, Università di Bologna [Bologna] (UNIBO), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Dall'olio F, Malagolini N, Chiricolo M, Trinchera M, Harduin-Lepers A, Université de Lille, University of Bologna/Università di Bologna, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], and Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, Erythrocytes, Oligosaccharides, Histo-blood group antigens, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Bleeding disorders, Biochemistry, Fucose, Epigenetic control, chemistry.chemical_compound, 0302 clinical medicine, MESH: Animals Blood Group Antigens/metabolism* Erythrocytes/metabolism* Humans N-Acetylgalactosaminyltransferases/metabolism* Oligosaccharides/metabolism, Cytotoxic T cell, Sialyl Lewis antigens, MESH: Animals, Bleeding disorder, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], MESH: Erythrocytes, Sialyl Lewis antigen, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 3. Good health, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Blood Group Antigens, N-Acetylgalactosaminyltransferases, Histo-blood group antigen, Biophysics, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: N-Acetylgalactosaminyltransferases, Natural killer cell, 03 medical and health sciences, Antigen, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Glycosyltransferase, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Blood Group Antigens, Glycosyltransferases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sialyl-Lewis A, Muscular dystrophy, Sialic acid, Sialyl-Lewis X, chemistry, biology.protein, MESH: Oligosaccharides
Abstract

International audience; BACKGROUND:The histo-blood group antigens are carbohydrate structures present in tissues and body fluids, which contribute to the definition of the individual immunophenotype. One of these, the Sd(a) antigen, is expressed on the surface of erythrocytes and in secretions of the vast majority of the Caucasians and other ethnic groups.SCOPE OF REVIEW:We describe the multiple and unsuspected aspects of the biology of the Sd(a) antigen and its biosynthetic enzyme β1,4-N-acetylgalactosaminyltransferase 2 (B4GALNT2) in various physiological and pathological settings.MAJOR CONCLUSIONS:The immunodominant sugar of the Sd(a) antigen is a β1,4-linked N-acetylgalactosamine (GalNAc). Its cognate glycosyltransferase B4GALNT2 displays a restricted pattern of tissue expression, is regulated by unknown mechanisms - including promoter methylation, and encodes at least two different proteins, one of which with an unconventionally long cytoplasmic portion. In different settings, the Sd(a) antigen plays multiple and unsuspected roles. 1) In colon cancer, its dramatic down-regulation plays a potential role in the overexpression of sialyl Lewis antigens, increasing metastasis formation. 2) It is involved in the lytic function of murine cytotoxic T lymphocytes. 3) It prevents the development of muscular dystrophy in various dystrophic murine models, when overexpressed in muscular fibers. 4) It regulates the circulating half-life of the von Willebrand factor (vWf), determining the onset of a bleeding disorder in a murine model.GENERAL SIGNIFICANCE:The expression of the Sd(a) antigen has a wide impact on the physiology and the pathology of different biological systems.

Published
2014

49. Identification of novel plasma glycosylation-associated markers of aging

Author

Catera, Mariangela, primary, Borelli, Vincenzo, additional, Malagolini, Nadia, additional, Chiricolo, Mariella, additional, Venturi, Giulia, additional, Reis, Celso A., additional, Osorio, Hugo, additional, Abruzzo, Provvidenza M., additional, Capri, Miriam, additional, Monti, Daniela, additional, Ostan, Rita, additional, Franceschi, Claudio, additional, and Dall’Olio, Fabio, additional

Published
2016
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50. Basi molecolari ed implicazioni fisio-patologiche dell'alterata glicosilazione di IgG nell'invecchiamento

Author

Dall'Olio, Fabio, Catera, Mariangela <1987>, Dall'Olio, Fabio, and Catera, Mariangela <1987>

Abstract

Introduzione: Le catene N-linked associate al principale sito di N-glicosilazione (Asn297) delle IgG sono di tipo bi-antennario e presentano una grande microeterogeneità in quanto una o entrambe le antenne possono terminare con uno o due residui di acido sialico, galattosio o N-acetilglucosammina ed essere core-fucosilate. Nell’invecchiamento e in malattie infiammatorie aumenta la percentuale di glicani associati alle catene pesanti delle IgG privi del galattosio terminale (IgG-G0). La glicosilazione enzimatica delle proteine è classicamente un processo intracellulare, sebbene recenti studi abbiano messo in evidenza la possibilità di una glicosilazione ecto-cellulare in quanto le piastrine sono ottimi donatori di nucleotidi-zuccheri. Scopo: Misurare le attività delle glicosiltrasferasi ST6Gal1 e B4GalT plasmatiche (potenzialmente responsabili della glicosilazione di proteine plasmatiche) in soggetti di entrambi i sessi e di età compresa tra 5 e 105 anni e correlarle con lo stato di glicosilazione di IgG circolanti (analizzato mediante lectin-blot) e il GlycoAge test, un noto marcatore di invecchiamento, espresso come il logaritmo del rapporto tra gli N-glicani agalattosilati e di-galattosilati associati a glicoproteine plasmatiche. Risultati e conclusioni: I dati ottenuti indicano che: 1) l’attività B4GalT si propone come nuovo marcatore di invecchiamento perché aumenta linearmente con l’età; 2) la ST6Gal1 è maggiormente espressa solo nei bambini e negli over 80; 3) le attività delle due glicosilatransferasi non risultano correlate in modo significativo né tra loro né con il GlycoAge test, indicando che questi tre marcatori siano espressioni di diversi quadri fisio-patologici legati all’invecchiamento; 4) con l’età si ha una predominanza di glicoforme di IgG pro-infiammatorie, ovvero prive dell’acido sialico, del galattosio terminali e del core fucose; 5) l’attività della ST6Gal1 e B4GalT risultano in controtendenza con il grado di sialilazione e galattosilazione de, Background: The N-linked chains associated with the main N- glycosylation site (Asn297) of IgG are bi- antennary type and present a great microheterogeneity because one or both antennas may end with one or two residues of sialic acid , galactose or N -acetilglucosammine and can be core – fucosilated. In aging and inflammatory diseases the percentage of glycans associated with heavy chains of IgG that lack terminal galactose (IgG - G0) increases. The enzymatic glycosylation of proteins is classically an intracellular process although recent studies have highlighted the possibility of extracellular glycosylation because the platelets are an excellent source of the sugar nucleotide – donors. Aim of study: To measure the activities of plasma glycosyltransferases ST6Gal1 and B4GalT (potentially responsible for the glycosylation of plasma proteins ) in individuals of both sexes and aged between 5 and 105 years, and correlate them with the state of glycosylation of circulating IgG (determined by lectin immunoblot analysis) and GlycoAge test, a know marker of aging that is the logarithm of the ratio between agalactosylated and di-galactosylated N-linked chains associated to plasma glycoprotein. Results and conclusions: Own results indicated that: 1) B4GalT acitvity is a new marker of aging because it increase linearly with age ; 2) ST6Gal1 activity is mostly expressed only in children and over 80; 3) The activity of the two glycosyltransferases does not relate each other and with the GlycoAge test indicating that all three of these markers are expressions of different physio- pathological frameworks related to aging; 4) during aging there is an abundance of pro-inflammatory glycoforms of IgG; 5) the activity of the ST6Gal1 and B4GalT are in contrast with the degree of sialylation and galactosylation of IgG , indicating that their glycosylation does not occur at the extracellular level .

Published
2015

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