Journal articles: 'Fucosylation'

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Fujita, Kazutoshi, Koji Hatano, Mamoru Hashimoto, Eisuke Tomiyama, Eiji Miyoshi, Norio Nonomura, and Hirotsugu Uemura. "Fucosylation in Urological Cancers." International Journal of Molecular Sciences 22, no. 24 (December 11, 2021): 13333. http://dx.doi.org/10.3390/ijms222413333.

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Fucosylation is an oligosaccharide modification that plays an important role in immune response and malignancy, and specific fucosyltransferases (FUTs) catalyze the three types of fucosylations: core-type, Lewis type, and H type. FUTs regulate cancer proliferation, invasiveness, and resistance to chemotherapy by modifying the glycosylation of signaling receptors. Oligosaccharides on PD-1/PD-L1 proteins are specifically fucosylated, leading to functional modifications. Expression of FUTs is upregulated in renal cell carcinoma, bladder cancer, and prostate cancer. Aberrant fucosylation in prostate-specific antigen (PSA) could be used as a novel biomarker for prostate cancer. Furthermore, elucidation of the biological function of fucosylation could result in the development of novel therapeutic targets. Further studies are needed in the field of fucosylation glycobiology in urological malignancies.

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Keeley, Tyler S., Shengyu Yang, and Eric Lau. "The Diverse Contributions of Fucose Linkages in Cancer." Cancers 11, no. 9 (August 24, 2019): 1241. http://dx.doi.org/10.3390/cancers11091241.

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Fucosylation is a post-translational modification of glycans, proteins, and lipids that is responsible for many biological processes. Fucose conjugation via α(1,2), α(1,3), α(1,4), α(1,6), and O’- linkages to glycans, and variations in fucosylation linkages, has important implications for cancer biology. This review focuses on the roles that fucosylation plays in cancer, specifically through modulation of cell surface proteins and signaling pathways. How L-fucose and serum fucosylation patterns might be used for future clinical diagnostic, prognostic, and therapeutic approaches will be discussed.

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Rydén, Ingvar, Peter Påhlsson, and Stefan Lindgren. "Diagnostic Accuracy of α1-Acid Glycoprotein Fucosylation for Liver Cirrhosis in Patients Undergoing Hepatic Biopsy." Clinical Chemistry 48, no. 12 (December 1, 2002): 2195–201. http://dx.doi.org/10.1093/clinchem/48.12.2195.

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Abstract Background: Increased fucosylation of serum glycoproteins has previously been reported in patients with liver disease. We analyzed α1-acid glycoprotein (AGP) fucosylation in serum samples from patients investigated for suspected liver disease to evaluate its value as a biochemical marker for liver cirrhosis. Methods: We used a novel lectin immunoassay adapted to the AutoDELFIA system to analyze AGP fucosylation in 261 consecutive patients admitted for liver biopsy at Malmö University Hospital in Southern Sweden. The results were compared with histopathologic findings. In addition, AGP fucosylation was compared with other biochemical markers described as useful in the diagnosis of liver cirrhosis. The biochemical markers were compared by ROC curve analysis. Results: AGP fucosylation was significantly (P <0.05) higher in patients with liver cirrhosis (n = 65) than in healthy controls (n = 72), patients with normal histology (n = 29), patients with steatosis only (n = 38), patients with viral or chronic hepatitis without cirrhosis (n = 71), and patients with other liver diseases without histologic signs of cirrhosis (n = 58). By calculating the AGP fucosylation index (AGP-FI = AGP fucosylation/AGP serum concentration), we obtained a high diagnostic accuracy. The areas under the ROC curves for AGP-FI were 0.83 and 0.74 for men and women, respectively, compared with 0.82 for hyaluronic acid and 0.77 for the aspartate aminotransferase/alanine aminotransferase ratio in both men and women. Conclusions: AGP fucosylation appears to be useful in identifying patients with liver cirrhosis among patients investigated for liver disease. The lectin immunoassay showed satisfactory reproducibility and is suitable for routine use in a clinical laboratory.

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Watson, Gregory, Daniel Lester, Hui Ren, Connor M. Forsyth, Elliot Medina, David Gonzalez Perez, Lancia Darville, et al. "Fucosylated Proteome Profiling Identifies a Fucosylated, Non-Ribosomal, Stress-Responsive Species of Ribosomal Protein S3." Cells 10, no. 6 (May 25, 2021): 1310. http://dx.doi.org/10.3390/cells10061310.

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Alterations in genes encoding for proteins that control fucosylation are known to play causative roles in several developmental disorders, such as Dowling-Degos disease 2 and congenital disorder of glycosylation type IIc (CDGIIc). Recent studies have provided evidence that changes in fucosylation can contribute to the development and progression of several different types of cancers. It is therefore important to gain a detailed understanding of how fucosylation is altered in disease states so that interventions may be developed for therapeutic purposes. In this report, we find that fucosylation occurs on many intracellular proteins. This is an interesting finding, as the fucosylation machinery is restricted to the secretory pathway and is thought to predominately affect cell-membrane-bound and secreted proteins. We find that Ribosomal protein S3 (RPS3) is fucosylated in normal tissues and in cancer cells, and that the extent of its fucosylation appears to respond to stress, including MAPK inhibitors, suggesting a new role in posttranslational protein function. Our data identify a new ribosome-independent species of fucosylated RPS3 that interacts with proteins involved in posttranscriptional regulation of RNA, such as Heterogeneous nuclear ribonucleoprotein U (HNRNPU), as well as with a predominance of non-coding RNAs. These data highlight a novel role for RPS3, which, given previously reported oncogenic roles for RPS3, might represent functions that are perturbed in pathologies such as cancer. Together, our findings suggest a previously unrecognized role for fucosylation in directly influencing intracellular protein functions.

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Gong, Huanle, Shoubao Ma, and Depei Wu. "Ex vivo fucosylation promotes the GVL effect of NK cells after Allo-HSCT." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 69.25. http://dx.doi.org/10.4049/jimmunol.202.supp.69.25.

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Abstract Recent studies demonstrated that ex vivo fucosylation can increase the persistence and anti-GVHD potency of Treg cells. Fucosylation also improves human cord blood engraftment. However, the role of fucosylation in graftversus- leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains unknown. Here, we established a murine GVL model by intravenously injecting luciferase (lus+)/yfp-expressing B-cell lymphoma (A20) cells and founded that adoptive transfer of fucosylated NK cells markedly prolonged the survival than control NK cells. Ex vivo fucosylation significantly upregulated IFN-γ production in NK cells and enhanced their cytotoxic activity. Flow cytometry analysis revealed that fucosylation promoted the infiltration of NK cells, which may be due to the elevated binding to CD62E. Further studies are needed to confirm the contribution of IFN-γ by using IFN-γ KO mice and investigate the detailed mechanisms of fucosylated NK cells in the regulation of GVL responses.

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Li, Tiezheng, David J. DiLillo, Stylianos Bournazos, John P. Giddens, Jeffrey V. Ravetch, and Lai-Xi Wang. "Modulating IgG effector function by Fc glycan engineering." Proceedings of the National Academy of Sciences 114, no. 13 (March 13, 2017): 3485–90. http://dx.doi.org/10.1073/pnas.1702173114.

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IgG antibodies contain a conserved N-glycosylation site on the Fc domain to which a complex, biantennary glycan is attached. The fine structures of this glycan modulate antibody effector functions by affecting the binding affinity of the Fc to diverse Fc receptor family members. For example, core fucosylation significantly decreases antibody-dependent cellular cytotoxicity (ADCC), whereas terminal α2,6-sialylation plays a critical role in the anti-inflammatory activity of human i.v. immunoglobulin therapy. The effect of specific combinations of sugars in the glycan on ADCC remains to be further addressed, however. Therefore, we synthesized structurally well-defined homogeneous glycoforms of antibodies with different combinations of fucosylation and sialylation and performed side-by-side in vitro FcγR-binding analyses, cell-based ADCC assays, and in vivo IgG-mediated cellular depletion studies. We found that core fucosylation exerted a significant adverse effect on FcγRIIIA binding, in vitro ADCC, and in vivo IgG-mediated cellular depletion, regardless of sialylation status. In contrast, the effect of sialylation on ADCC was dependent on the status of core fucosylation. Sialylation in the context of core fucosylation significantly decreased ADCC in a cell-based assay and suppressed antibody-mediated cell killing in vivo. In contrast, in the absence of fucosylation, sialylation did not adversely impact ADCC.

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Antonarelli, Gabriele, Valentina Pieri, Francesca Maria Porta, Nicola Fusco, Gaetano Finocchiaro, Giuseppe Curigliano, and Carmen Criscitiello. "Targeting Post-Translational Modifications to Improve Combinatorial Therapies in Breast Cancer: The Role of Fucosylation." Cells 12, no. 6 (March 8, 2023): 840. http://dx.doi.org/10.3390/cells12060840.

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Various tumors rely on post-translational modifications (PTMs) to promote invasiveness and angiogenesis and to reprogram cellular energetics to abate anti-cancer immunity. Among PTMs, fucosylation is a particular type of glycosylation that has been linked to different aspects of immune and hormonal physiological functions as well as hijacked by many types of tumors. Multiple tumors, including breast cancer, have been linked to dismal prognoses and increased metastatic potential due to fucosylation of the glycan core, namely core-fucosylation. Pre-clinical studies have examined the molecular mechanisms regulating core-fucosylation in breast cancer models, its negative prognostic value across multiple disease stages, and the activity of in vivo pharmacological inhibition, instructing combinatorial therapies and translation into clinical practice. Throughout this review, we describe the role of fucosylation in solid tumors, with a particular focus on breast cancer, as well as physiologic conditions on the immune system and hormones, providing a view into its potential as a biomarker for predicating or predicting cancer outcomes, as well as a potential clinical actionability as a biomarker.

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Lin, Hongli, Dapeng Wang, Taihua Wu, Cui Dong, Nan Shen, Yuan Sun, Yanling Sun, Hua Xie, Nan Wang, and Lujuan Shan. "Blocking core fucosylation of TGF-β1 receptors downregulates their functions and attenuates the epithelial-mesenchymal transition of renal tubular cells." American Journal of Physiology-Renal Physiology 300, no. 4 (April 2011): F1017—F1025. http://dx.doi.org/10.1152/ajprenal.00426.2010.

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Posttranslational modification of proteins could regulate their multiple biological functions. Transforming growth factor-β receptor I and II (ALK5 and TGF-βRII), which are glycoproteins, play important roles in the renal tubular epithelial-mesenchymal transition (EMT). In the present study, we examined the role of core fucosylation of TGF-βRII and ALK5, which is regulated by α-1,6 fucosyltransferase (Fut8), in the process of EMT of cultured human renal proximal tubular epithelial (HK-2) cells. The typical cell model of EMT induced by TGF-β1 was constructed to address the role of core fucosylation in EMT. Core fucosylation was found to be essential for both TGF-βRII and ALK5 to fulfill their functions, and blocking it with Fut8 small interfering RNA greatly reduced the phosphorylation of Smad2/3 protein, caused the inactivation of TGF-β/Smad2/3 signaling, and resulted in remission of EMT. More importantly, even with high levels of expressions of TGF-β1, TGF-βRII, and ALK5, blocking core fucosylation also could attenuate the EMT of HK-2 cells. Thus blocking core fucosylation of TGF-βRII and ALK5 may attenuate EMT independently of the expression of these proteins. This study may provide new insight into the role of glycosylation in renal interstitial fibrosis. Furthermore, core fucosylation may be a novel potential therapeutic target for treatment of renal tubular EMT.

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MILLS, Philippa, Kevin MILLS, Peter CLAYTON, Andrew JOHNSON, David WHITEHOUSE, and Bryan WINCHESTER. "Congenital disorders of glycosylation type I leads to altered processing of N-linked glycans, as well as underglycosylation." Biochemical Journal 359, no. 2 (October 8, 2001): 249–54. http://dx.doi.org/10.1042/bj3590249.

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The N-linked glycans on transferrin and α1-antitrypsin from patients with congenital disorders of glycosylation type I have increased fucosylation and branching relative to normal controls. The elevated levels of monofucosylated biantennary glycans are probably due to increased α-(1 → 6) fucosylation. The presence of bi- and trifucosylated triantennary and tetra-antennary glycans indicated that peripheral α-(1 → 3), as well as core α-(1 → 6), fucosylation is increased. Altered processing was observed on both the fully and underglycosylated glycoforms.

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Moriwaki, Kenta. "Fucosylation and gastrointestinal cancer." World Journal of Hepatology 2, no. 4 (2010): 151. http://dx.doi.org/10.4254/wjh.v2.i4.151.

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Smith, Peter L., Jay T. Myers, Clare E. Rogers, Lan Zhou, Bronia Petryniak, Daniel J. Becker, Jonathon W. Homeister, and John B. Lowe. "Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus." Journal of Cell Biology 158, no. 4 (August 19, 2002): 801–15. http://dx.doi.org/10.1083/jcb.200203125.

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Glycoprotein fucosylation enables fringe-dependent modulation of signal transduction by Notch transmembrane receptors, contributes to selectin-dependent leukocyte trafficking, and is faulty in leukocyte adhesion deficiency (LAD) type II, also known as congenital disorder of glycosylation (CDG)-IIc, a rare human disorder characterized by psychomotor defects, developmental abnormalities, and leukocyte adhesion defects. We report here that mice with an induced null mutation in the FX locus, which encodes an enzyme in the de novo pathway for GDP–fucose synthesis, exhibit a virtually complete deficiency of cellular fucosylation, and variable frequency of intrauterine demise determined by parental FX genotype. Live-born FX(−/−) mice exhibit postnatal failure to thrive that is suppressed with a fucose-supplemented diet. FX(−/−) adults suffer from an extreme neutrophilia, myeloproliferation, and absence of leukocyte selectin ligand expression reminiscent of LAD-II/CDG-IIc. Contingent restoration of leukocyte and endothelial selectin ligand expression, general cellular fucosylation, and normal postnatal physiology is achieved by modulating dietary fucose to supply a salvage pathway for GDP–fucose synthesis. Conditional control of fucosylation in FX(−/−) mice identifies cellular fucosylation events as essential concomitants to fertility, early growth and development, and leukocyte adhesion.

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Verbij, Fabian C., Eva Stokhuijzen, Paul H. P. Kaijen, Floris van Alphen, Alexander B. Meijer, and Jan Voorberg. "Identification of glycans on plasma-derived ADAMTS13." Blood 128, no. 21 (November 24, 2016): e51-e58. http://dx.doi.org/10.1182/blood-2016-06-720912.

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Key Points ADAMTS13 contains complex type N-linked glycans, which contain terminal mannose, sialic acids, and fucose residues. TSP1 repeats are modified by O-fucosylation and C-mannosylation; O-fucosylation was also observed in the disintegrin domain.

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Doud, Emma H., Trupti Shetty, Melissa Abt, Amber L. Mosley, Timothy W. Corson, Anand Mehta, and Elizabeth S. Yeh. "NF-κB Signaling Is Regulated by Fucosylation in Metastatic Breast Cancer Cells." Biomedicines 8, no. 12 (December 12, 2020): 600. http://dx.doi.org/10.3390/biomedicines8120600.

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A growing body of evidence indicates that the levels of fucosylation correlate with breast cancer progression and contribute to metastatic disease. However, very little is known about the signaling and functional outcomes that are driven by fucosylation. We performed a global proteomic analysis of 4T1 metastatic mammary tumor cells in the presence and absence of a fucosylation inhibitor, 2-fluorofucose (2FF). Of significant interest, pathway analysis based on our results revealed a reduction in the NF-κB and TNF signaling pathways, which regulate the inflammatory response. NF-κB is a transcription factor that is pro-tumorigenic and a prime target in human cancer. We validated our results, confirming that treatment of 4T1 cells with 2FF led to a decrease in NF-κB activity through increased IκBα. Based on these observations, we conclude that fucosylation is an important post-translational modification that governs breast cancer cell signaling.

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Zimmermann, Martina, Janike Ehret, Harald Kolmar, and Aline Zimmer. "Impact of Acetylated and Non-Acetylated Fucose Analogues on IgG Glycosylation." Antibodies 8, no. 1 (January 10, 2019): 9. http://dx.doi.org/10.3390/antib8010009.

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The biological activity of therapeutic antibodies is highly influenced by their glycosylation profile. A valuable method for increasing the cytotoxic efficacy of antibodies, which are used, for example, in cancer treatment, is the reduction of core fucosylation, as this enhances the elimination of target cells through antibody-dependent cell-mediated cytotoxicity. Development of fucose analogues is currently the most promising strategy to reduce core fucosylation without cell line engineering. Since peracetylated sugars display enhanced cell permeability over the highly polar free hydroxy sugars, this work sought to compare the efficacy of peracetylated sugars to their unprotected forms. Two potent fucose analogues, 2-deoxy-2-fluorofucose and 5-alkynylfucose, and their acetylated forms were compared for their effects on fucosylation. 5-alkynylfucose proved to be more potent than 2-deoxy-2-fluorofucose at reducing core fucosylation but was associated with a significant higher incorporation of the alkynylated fucose analogue. Acetylation of the sugar yielded only slightly lower fucosylation levels suggesting that acetylation has a minor impact on cellular entry. Even though the efficacy of all tested components was confirmed, results presented in this study also show a significant incorporation of unnatural fucose analogues into the glycosylation pattern of the produced IgG, with unknown effect on safety and potency of the monoclonal antibody.

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Regoeczi, Erwin, J. Michael Kay, Paul A. Chindemi, Ouahida Zaimi, and Kaye L. Suyama. "Transferrin glycosylation in hypoxia." Biochemistry and Cell Biology 69, no. 4 (April 1, 1991): 239–44. http://dx.doi.org/10.1139/o91-036.

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The aim of this study was to examine the effect of reduced O2 tension on the glycosylation of transferrin. Rats were placed in a hypobaric chamber (380 mmHg) that corresponded to an altitude of 5486 m above sea level for 21 days. The animals responded with marked increases in hematocrit (from 44 to 76%) and cardiac weight, and with reductions in the concentration of plasma transferrin averaging 15%. Analyses of their plasma transferrin by serial anion-exchange and lectin affinity chromatography revealed no changes in the extent of glycan branching. However, there was a moderate rise in the proportion of fucosylated transferrin molecules (fucosylation index) and a slight decrease in the transferrin fraction bearing a tetrasialylated biantennary glycan. The fucosylation index correlated positively with plasma transferrin concentrations in the test animals, but not in the controls. In contradistinction to the situation with transferrin, hypoxic rats exhibited a reduced fucosylation index of immunoglobulin G.Key words: fucosylation index, hypoxia, immunoglobulin G, lectin affinity chromatography, transferrin.

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Alatrash, Gheath, Mao Zhang, Na Qiao, Pariya Sukhumalchandra, Madhushree Zope, Anne V. Philips, Alexander Perakis, et al. "Fucosylated Antigen-Specific Cytotoxic T Lymphocytes Demonstrate Enhanced Killing of Leukemia Targets." Blood 126, no. 23 (December 3, 2015): 1888. http://dx.doi.org/10.1182/blood.v126.23.1888.1888.

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Abstract Introduction Immunotherapy using cytotoxic T lymphocytes (CTL) has shown efficacy in the management of leukemia. However the efficacy of CTL, whether they are engineered and adoptively transferred or administered as part of allogeneic stem cell transplantation, must be balanced by their off-target toxicities, which at times can be lethal. Fucosylation, which is mediated by fucosyl transferases, is a process by which fucose sugar groups are added to cell surface receptors. Fucosylated T cells have been shown to preferentially home to inflamed tissues, including bone marrow. In view of recent data showing that fucosylation with fucosyltransferase (FT)-VI facilitates homing of regulatory T cells (T-regs) to inflamed tissues and cord blood engraftment into the bone marrow, we hypothesized that fucosylation could enhance the efficacy of CTL that target leukemia antigens. In this study, we tested whether ex vivo fucosylation of CTL that target the HLA-A2 restricted leukemia peptides, CG1 (derived from cathepsin G) and PR1 (derived from neutrophil elastase and proteinase 3), with the novel enzyme FT-VII enhances their migration and anti-leukemia functions. Experimental design CG1- and PR1-CTL were generated using standard methodologies. Fucosylation was achieved by incubating T cells with FTVII enzyme and GDP fucose (Targazyme). To study migration, fucosylated and non-fucosylated CTL were passed through chambers coated with a HUVEC barrier and migrated CTL were detected using cell fluorescence. To examine CTL surface markers, cells were stained for standard co-stimulatory and adhesion molecules and were analyzed using flow cytometry. Calcein AM cytotoxicity assays were used to determine the effects of fucosylation on CTL killing of target cells. In vitro effects of fucosylation on leukemia-CTL specificity was accomplished using standard CFU assays. For in vivo assessment of fucosylation on activity of CTL, NSG mice were engrafted with U937-A2 human acute myeloid leukemia (AML) cells or primary AML and were treated with intravenous injections of 5.0 x 105 fucosylated or non-fucosylated CTL. Mice were followed twice weekly and were sacrificed for bone marrow and tissue analysis at prespecified time points or when they became moribund. Results Fucosylated CG1-CTL and PR1-CTL showed approximately 2-fold higher migration through the HUVEC cell barrier compared to non-fucosylated CTL. Analysis of T cell surface expression of chemokine/adhesion molecules showed an approximately a 5-fold increase in CD49d and CD195, and a 50% increase in CXCR1 and CXCR3 following fucosylation. Fucosylation enhanced the cytotoxicity of leukemia specific-CTL against primary HLA-A2+ leukemia and HLA-A2+ U937 cells at increasing effector to target ratios. For primary patient AML, we show enhanced leukemia killing by fucosylated-PR1-CTL in comparison with non-fucosylated-PR1-CTL at the 20:1 effector to target (E:T) ratio (25-fold higher killing ) and the 10:1 E:T ratio (4-fold higher killing). Similar results were seen using the U937-A2 AML cell line favoring fucosylated-CG1-CTL: 20-fold higher killing at 20:1 E:T ratio and a 9-fold higher killing at the 10:1 E:T ratio. In vitro CFU assays using HLA-A2+ healthy donor bone marrow showed no change in the specificity of the antigen specific CTL following fucosylation. Specifically we show 283 and 295 colonies in the fucosylated and non-fucosylated CG1-CTL groups, respectively (P >0.05). These were also compared to irrelevant peptide HIV-CTL, which demonstrated 286 and 269 CFUs in the fucosylated and non-fucosylated HIV-CTL groups, respectively (P >0.05). In vivo experiments using CG1-CTL against primary AML showed 5-fold higher killing of AML by fucosylated CTL vs. non-fucosylated CTL. Similar results were also seen using U937-A2 AML targets. Conclusion Fucosylation with FT-VII enhances the efficacy of leukemia-targeting CTL against primary human AML and AML cell lines. These data demonstrate a novel approach to enhance the efficacy of antigen specific CTL that could be used in adoptive cellular immunotherapy approaches for leukemia. Disclosures No relevant conflicts of interest to declare.

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Onishi, Toshihiro, Maria Berg, Robert Reger, Leonard Miller, Steve Wolpe, Lynnet Koh, and Richard Childs. "Forced Fucosylation With ASC-101 Enhances The Binding Of Ex Vivo Expanded Human NK Cells To E-Selectin: A Novel Method To Improve The Homing Of Adoptively Transferred NK Cells To The Bone Marrow In Patients With Hematological Malignancies." Blood 122, no. 21 (November 15, 2013): 4499. http://dx.doi.org/10.1182/blood.v122.21.4499.4499.

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Introduction The ability of adoptively infused NK cells to home and traffic to the microenvironment where the tumor resides may be a critical determinant of their ability to mediate clinically meaningful anti-tumor effects. The initial step in leukocyte emigration from post-capillary venules, referred to as “tethering”, is a low-affinity interaction between leukocyte ligands with selectins expressed on endothelial cells. Since E-selectin is constitutively expressed on endothelium of skin and bone marrow in humans, leukocyte recruitment to bone marrow is thought to be largely dependent on E-selectin-binding. Among E-selectin ligands, only ligands bearing sialyl Lewis X with a terminal fucose (fucosylated) are functional forms that actively bind to E-selectin. One of the pitfalls of ex vivo NK cell expansion for adoptive infusion in humans is that expanded NK cells express predominantly non-fucosylated E-selectin ligands. We hypothesized that ex vivo fucosylation could enhance the binding capacity of E-selectin ligands on NK cells improving their homing into bone marrow where hematological malignancies reside. Methods CD56+/CD3- NK cells were isolated from normal human subjects by immuno-magnetic bead selection and were expanded ex vivo over 7-21 days by co-culturing with irradiated EBV-LCL feeder cells in IL-2 containing medium. Expanded NK cells were incubated for 30 minutes at room temperature with GDP-fucose and alpha1,3 fucosyltransferase-VI (ASC-101). The levels of fucosylation were determined by CLA surface expression measured by flow cytometry using the antibody HECA-452. After fucosylation, NK cells were analyzed by flow cytometry to assess for phenotype changes, viability and stability of fucosylation. Chromium release assays were performed to assess NK cell cytotoxicity against tumor cells. To determine whether fucosylated NK cells had enhanced binding to E-selectin, the binding capacity of NK cells to human recombinant E-selectin/Fc Chimera protein was evaluated by flow cytometry. Results Expanded human NK cells had low levels of baseline fucosylation, ranging from only 10-25%. Expanded NK cells were successfully fucosylated with ASC-101 in a dose-dependent manner (figure); the MFI of CLA on NK cells peaked at 25 ug/ml of ASC-101, with nearly 100% of NK cells being fucosylated (CLA positive). Fucosylation did not affect NK cell viability nor was it associated with changes in NK cell phenotype including surface expression of CD16, CD56, KIR2DL1, KIR2DL2/3, KIR3DL1, NKG2A, NKG2D, TRAIL, perforin, or granzymes A/B. Ex vivo cell culture showed fucosylation was sustained at nearly 100% for 48 hours, but then rapidly declined returning to baseline levels by 96 hours. NK cell cytotoxicity against tumor targets including K562 cells and myeloma cells was preserved and unaffected by fucosylation. Fucosylation significantly enhanced the binding capacity of NK cells to human E-selectin. Further, NK cell binding to recombinant human E-selectin/Fc chimera protein directly correlated with the degree of NK cell fucosylation (figure), which was dose-dependent on the ASC-101 concentration. The effects of forced fucosylation on the ability of human NK cells to home to the bone marrow following adoptive transfer into immuno-deficient mice is currently being explored. Conclusion Expanded NK cells primarily express non-glycosylated ligands for E-selectin, potentially limiting their ability to home to the bone marrow following adoptive transfer in humans with hematological malignancies. Ligands for E-selectin on the surface of expanded NK cells can be glycosylated ex vivo rapidly and to high degrees using ASC-101, significantly enhancing their ability to bind E-selectin. These data suggest forced fucosylation of NK cells could be used as a novel approach to improve the antitumor effects of adoptive NK cell infusions in patients with hematological malignancies. Disclosures: Miller: America Stem Cell Inc: Employment. Wolpe:American Stem Cell, Inc: Employment. Koh:America Stem Cell Inc: Employment.

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Demus, Daniel, Paulina A. Urbanowicz, Richard A. Gardner, Haiyang Wu, Agata Juszczak, Tamara Štambuk, Edita Pape Medvidović, et al. "Development of an exoglycosidase plate-based assay for detecting α1-3,4 fucosylation biomarker in individuals with HNF1A-MODY." Glycobiology 32, no. 3 (October 25, 2021): 230–38. http://dx.doi.org/10.1093/glycob/cwab107.

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Abstract Maturity-onset diabetes of the young due to hepatocyte nuclear factor-1 alpha variants (HNF1A-MODY) causes monogenic diabetes. Individuals carrying damaging variants in HNF1A show decreased levels of α1-3,4 fucosylation, as demonstrated on antennary fucosylation of blood plasma N-glycans. The excellent diagnostic performance of this glycan biomarker in blood plasma N-glycans of individuals with HNF1A-MODY has been demonstrated using liquid chromatography methods. Here, we have developed a high-throughput exoglycosidase plate-based assay to measure α1-3,4 fucosylation levels in blood plasma samples. The assay has been optimized and its validity tested using 1000 clinical samples from a cohort of individuals with young-adult onset diabetes including cases with HNF1A-MODY. The α1-3,4 fucosylation levels in blood plasma showed a good differentiating power in identifying cases with damaging HNF1A variants, as demonstrated by receiver operating characteristic curve analysis with the AUC values of 0.87 and 0.95. This study supports future development of a simple diagnostic test to measure this glycan biomarker for application in a clinical setting.

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Trummer, Arne, Dennis Rataj, Sonja Werwitzke, and Andreas Tiede. "Comparison Of Autologous Microparticles and Fucosyltransferase-7 For Adhesion Improvement Of Hematopoietic Stem Cells To Bone Marrow Endothelial Cells In a Microfluidic Flow Chamber." Blood 122, no. 21 (November 15, 2013): 2000. http://dx.doi.org/10.1182/blood.v122.21.2000.2000.

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Abstract The improvement of graft function and time to engraftment might help to reduce infection-related mortality in stem cell transplantation (SCT). While the concept of stem cells fucosylation for accelerated engraftment has already reached clinical study phase (for cord blood transplantation; NCT01471067), own previous work has shown an association between engraftment time and circulating microparticles bearing P-Selectin and P-Selectin glycoprotein ligand 1 (PSGL-1). PSGL-1 contains the sialyl Lewis x (CD15s) antigen that requires fucosylation for optimal binding of P- and E-Selectin on endothelial cells. We therefore hypothesized that addition of microparticles (MP) might enhance adhesion of human stem cells (HSC) to bone marrow endothelial cells and that MP might have synergistic effects in combination with stem cell fucosylation. HSC were obtained from apheresis products of allogeneic donors, purified by Ficoll and magnetic bead separation for CD34, stained with calcein AM and perfused through an automated microfluidic flow chamber (Bioflux 200, Fluxionbio, USA) covered with a confluent layer of an immortalized human bone marrow endothelial cell line (HBMEC). Photos (and videos) were taken using a fluorescence microscope at start, 5 min and 10 min and analyzed for adherent HSC across the whole chamber (about 1.5 sqmm) using ImageJ software. Autologous MP were generated by addition of calcimycin to apheresis and isolation of MP by centrifugation. For control experiments, one part of the MP solution was passed through a 0,2µm-filter to remove MP. MP concentration (mean: 1362/µl) was assessed by detection of Annexin V binding in flow cytometry, using TrucountBeads® for quantification. Fucosylation was performed by 1h incubation of isolated CD34+ stem cells with GDP-fucose and fucosyltransferase 7 (FUT7). Successful fucosylation was controlled by CD15s staining of HSC in flow cytometry. Results of seven experiments (in duplicate) demonstrated the highest number of adherent HSC in the MPpositiv/FUT7negativ preparation (median: 32 HSC/sqmm; range: 15-78), followed by MPpositiv/FUT7positiv (30 HSC/sqmm; range: 16-38), MPnegativ/FUT7positiv (median: 25/sqmm; range: 11-27) and MPnegativ/FUT7negativ (20 HSC/sqmm; range: 0-22). Comparison of the MPpositiv/FUT7negativ and MPnegativ/FUT7negativ as well as the MPpositiv/FUT7positiv and MPpositiv/FUT7negativ preparations showed statistically significant differences in Wilcoxon rank test (p<.05) while comparison of MPpositiv/FUT7positiv vs. MPnegativ/FUT7positiv and MPnegativ/FUT7positiv vs. MPnegativ/FUT7negativ preparations did not. In summary, these results demonstrate that MP can improve HSC adhesion to bone marrow endothelial cells similar to fucosylation. The effect of fucosylation on HSC adhesion appears to be mediated by MP. However, there is not a synergistic effect between MP and fucosylation. Disclosures: No relevant conflicts of interest to declare.

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Scanlon, Seth Thomas. "IgG fucosylation predicts dengue severity." Science 372, no. 6546 (June 3, 2021): 1051.17–1053. http://dx.doi.org/10.1126/science.372.6546.1051-q.

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Wing, David R. "Core fucosylation in honeybee venom." Glycobiology 4, no. 5 (1994): 548–49. http://dx.doi.org/10.1093/glycob/4.5.548.

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Ma, Bing, Joanne L. Simala-Grant, and Diane E. Taylor. "Fucosylation in prokaryotes and eukaryotes." Glycobiology 16, no. 12 (September 14, 2006): 158R—184R. http://dx.doi.org/10.1093/glycob/cwl040.

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Wang, Qiong, and Michael J. Betenbaugh. "Metabolic engineering of CHO cells to prepare glycoproteins." Emerging Topics in Life Sciences 2, no. 3 (October 18, 2018): 433–42. http://dx.doi.org/10.1042/etls20180056.

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As a complex and common post-translational modification, N-linked glycosylation affects a recombinant glycoprotein's biological activity and efficacy. For example, the α1,6-fucosylation significantly affects antibody-dependent cellular cytotoxicity and α2,6-sialylation is critical for antibody anti-inflammatory activity. Terminal sialylation is important for a glycoprotein's circulatory half-life. Chinese hamster ovary (CHO) cells are currently the predominant recombinant protein production platform, and, in this review, the characteristics of CHO glycosylation are summarized. Moreover, recent and current metabolic engineering strategies for tailoring glycoprotein fucosylation and sialylation in CHO cells, intensely investigated in the past decades, are described. One approach for reducing α1,6-fucosylation is through inhibiting fucosyltransferase (FUT8) expression by knockdown and knockout methods. Another approach to modulate fucosylation is through inhibition of multiple genes in the fucosylation biosynthesis pathway or through chemical inhibitors. To modulate antibody sialylation of the fragment crystallizable region, expressions of sialyltransferase and galactotransferase individually or together with amino acid mutations can affect antibody glycoforms and further influence antibody effector functions. The inhibition of sialidase expression and chemical supplementations are also effective and complementary approaches to improve the sialylation levels on recombinant glycoproteins. The engineering of CHO cells or protein sequence to control glycoforms to produce more homogenous glycans is an emerging topic. For modulating the glycosylation metabolic pathways, the interplay of multiple glyco-gene knockouts and knockins and the combination of multiple approaches, including genetic manipulation, protein engineering and chemical supplementation, are detailed in order to achieve specific glycan profiles on recombinant glycoproteins for superior biological function and effectiveness.

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Zhang, Ao, Steven J. Berardinelli, Christina Leonhard-Melief, Deepika Vasudevan, Ta-Wei Liu, Andrew Taibi, Sharee Giannone, Suneel S. Apte, Bernadette C. Holdener, and Robert S. Haltiwanger. "O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations." Journal of Biological Chemistry 295, no. 46 (September 10, 2020): 15742–53. http://dx.doi.org/10.1074/jbc.ra120.014557.

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ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder, geleophysic dysplasia 1 (GPHYSD1), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 is a matricellular protein previously shown to interact with latent transforming growth factor-β binding protein 1 and influence assembly of fibrillin 1 microfibrils. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for O-fucosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose–modified TSRs are subsequently elongated to a glucose β1-3-fucose (GlcFuc) disaccharide by β1,3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS), which is characterized by skeletal defects similar to GPHYSD1. Several ADAMTSL2 TSRs also have consensus sequences for C-mannosylation. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used MS to identify glycan modifications at predicted consensus sequences on mouse ADAMTSL2. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2−/− but not in B3GLCT−/− cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients. In contrast, secretion was significantly reduced for ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6), and S641L eliminated O-fucosylation of TSR3. These results provide evidence that abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion.

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Li, Jun, Hui-Chen Hsu, PingAr Yang, Qi Wu, David Spalding, and John Mountz. "Fucosylation is a hallmark of inflammatory macrophages and a novel therapeutic target in rheumatoid arthritis (P5137)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 137.10. http://dx.doi.org/10.4049/jimmunol.190.supp.137.10.

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Abstract Inflammatory macrophages (MΦ) play an important role in rheumatoid arthritis (RA). Fucosylation is a regulator of inflammation and we have observed a highly positive correlation between Fucosyltransferases (Fut)1 or Fut3 and Tnfα (p=0.0001) in RA synovial tissues. In sorted cells from human RA synovial fluid, Fut1 and Fut3 was highly expressed in M1 inflammatory MΦ (CD68+CD80+), but not in M2 MΦ (CD68+CD80-), synovial fibroblasts, Th1, Th17, and other T cells (p<0.01, n=5). Fucosylation inhibitor, 2-Deoxy-D-galactose (2-D-gal), precluded the differentiation of M1 MΦ derived by GM-CSF from mouse bone marrow or human PBMC monocytes, strongly indicating the indispensable role of fucosylation in M1 MΦ differentiation. Additionally, phalloidin staining showed 2-D-gal disrupted MΦ actin, suggesting a potential effect of fucosylation in antigen processing and presentation. Indeed, 2-D-gal treatment of fully differentiated M1 MΦ for 2 days dramatically reduced their uptake, processing and presentation of GFP-Eα (from I-Edα) and FITC-CII antigens in a dose dependent manner (p<0.01). In vivo, 2-D-gal dramatically blocked the bovine CII-induced arthritis in DBA/1J mice (scores 9.5±1.7 vs 0.5± 0.3, p<0.01) with reduced inflammatory MΦ in draining LN (1.3±0.3% vs 0.5±0.1%, p<0.05), decreased TNF-α (130 vs 39 pg/ml, p<0.05), and anti-CII in the serum. Our study indicated that M1 MΦ differentiation and function is orchestrated by fucosylation, which is a novel therapeutic target in RA.

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Kapur, Rick, Anne Vestrheim, Carolien AM Koeleman, Leendert Porcelijn, Dave Jackson, Belinda Kumpel, André M. Deelder, et al. "Skewing towards Decreased Fc-Fucosylation of Platelet-Alloantibodies in Pregnancy." Blood 120, no. 21 (November 16, 2012): 3331. http://dx.doi.org/10.1182/blood.v120.21.3331.3331.

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Abstract Abstract 3331 IgG-antibody responses during pregnancy against human platelet antigens (HPA) of the fetus can result in fetal or neonatal alloimmune thrombocytopenia (FNAIT) with various clinical scenarios, as patients can be asymptomatic, suffer from petechiae, major organ bleedings, or even intracranial hemorrhages. Various biological activities of IgG including antibody-dependent cellular cytotoxicity (ADCC) can be modulated by the structural features of the N-glycans in the Fc-part. The extent of sialylation, galactosylation, and fucosylation have been described to affect the binding of IgG to Fc-receptors (FcγR). Fucosylation is particularly important, as a lack of IgG-Fc-fucose has >50 times greater affinity and associated activity through FcγRIIIa, as compared to fucosylated IgG, which normally comprises >90% of normal serum IgG. By extensive analysis of the Fc-glycosylation using mass spectrometry, we found slightly increased levels of galactosylation (p<0.0001) but markedly decreased levels of core-fucosylation (p<0.0001) of the pathogenic IgG (anti-HPA1a) formed in FNAIT compared to the total IgG1 in the same patients. This unique response led us to question whether lack of fucose was specific for antibodies formed against platelets or due to the immune response during pregnancy. Analyses of anti-HLA antibodies formed after platelet transfusion (refractory thrombocytopenia) unveiled a similar increase in anti-platelet IgG galactosylation (p: 0.0002) as seen in FNAIT, but without any change in IgG fucosylation. Also when analyzing autoantibodies to platelet-glycoprotein IIb/IIIa in auto-immune thrombocytopenia (ITP), we could not detect any changes in IgG-glycosylation including fucosylation. We therefore conclude that the atypical fucosylation seen in the FNAIT-anti-platelet response is related to the immune milieu defined by pregnancy. This infuences IgG effector functions, including ADCC activity and may have a profound effect on disease severity and prognosis of alloimmune-mediated reactions against fetal cells and tissues. Disclosures: No relevant conflicts of interest to declare.

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Holst, Stephanie, Jennifer Wilding, Kamila Koprowska, Yoann Rombouts, and Manfred Wuhrer. "N-Glycomic and Transcriptomic Changes Associated with CDX1 mRNA Expression in Colorectal Cancer Cell Lines." Cells 8, no. 3 (March 22, 2019): 273. http://dx.doi.org/10.3390/cells8030273.

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The caudal-related homeobox protein 1 (CDX1) is a transcription factor, which is important in the development, differentiation, and homeostasis of the gut. Although the involvement of CDX genes in the regulation of the expression levels of a few glycosyltransferases has been shown, associations between glycosylation phenotypes and CDX1 mRNA expression have hitherto not been well studied. Triggered by our previous study, we here characterized the N-glycomic phenotype of 16 colon cancer cell lines, selected for their differential CDX1 mRNA expression levels. We found that high CDX1 mRNA expression associated with a higher degree of multi-fucosylation on N-glycans, which is in line with our previous results and was supported by up-regulated gene expression of fucosyltransferases involved in antenna fucosylation. Interestingly, hepatocyte nuclear factors (HNF)4A and HNF1A were, among others, positively associated with high CDX1 mRNA expression and have been previously proven to regulate antenna fucosylation. Besides fucosylation, we found that high CDX1 mRNA expression in cancer cell lines also associated with low levels of sialylation and galactosylation and high levels of bisection on N-glycans. Altogether, our data highlight a possible role of CDX1 in altering the N-glycosylation of colorectal cancer cells, which is a hallmark of tumor development.

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Yoon, Chang Ho, Jin Suk Ryu, Jung Hwa Ko, and Joo Youn Oh. "Inhibition of Aberrant α(1,2)-Fucosylation at Ocular Surface Ameliorates Dry Eye Disease." International Journal of Molecular Sciences 22, no. 15 (July 23, 2021): 7863. http://dx.doi.org/10.3390/ijms22157863.

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Fucosylation is involved in a wide range of biological processes from cellular adhesion to immune regulation. Although the upregulation of fucosylated glycans was reported in diseased corneas, its implication in ocular surface disorders remains largely unknown. In this study, we analyzed the expression of a fucosylated glycan on the ocular surface in two mouse models of dry eye disease (DED), the NOD.B10.H2b mouse model and the environmental desiccating stress model. We furthermore investigated the effects of aberrant fucosylation inhibition on the ocular surface and DED. Results demonstrated that the level of type 2 H antigen, an α(1,2)-fucosylated glycan, was highly increased in the cornea and conjunctiva both in NOD.B10.H2b mice and in BALB/c mice subjected to desiccating stress. Inhibition of α(1,2)-fucosylation by 2-deoxy-D-galactose (2-D-gal) reduced corneal epithelial defects and increased tear production in both DED models. Moreover, 2-D-gal treatment suppressed the levels of inflammatory cytokines in the ocular surface and the percentages of IFN-γ+CD4+ cells in draining lymph nodes, whereas it did not affect the number of conjunctival goblet cells, the MUC5AC level or the meibomian gland area. Together, the findings indicate that aberrant fucosylation underlies the pathogenesis of DED and may be a novel target for DED therapy.

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Zhou, Lan, Lebing Wei Li, Quanjian Yan, Bronislawa Petryniak, Yunfang Man, Charles Su, Jeongsup Shim, Stephanie Chervin, and John B. Lowe. "Notch-dependent control of myelopoiesis is regulated by fucosylation." Blood 112, no. 2 (July 15, 2008): 308–19. http://dx.doi.org/10.1182/blood-2007-11-115204.

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Abstract Cell-cell contact–dependent mechanisms that modulate proliferation and/or differentiation in the context of hematopoiesis include mechanisms characteristic of the interactions between members of the Notch family of signal transduction molecules and their ligands. Whereas Notch family members and their ligands clearly modulate T lymphopoietic decisions, evidence for their participation in modulating myelopoiesis is much less clear, and roles for posttranslational control of Notch-dependent signal transduction in myelopoiesis are unexplored. We report here that a myeloproliferative phenotype in FX−/− mice, which are conditionally deficient in cellular fucosylation, is consequent to loss of Notch-dependent signal transduction on myeloid progenitor cells. In the context of a wild-type fucosylation phenotype, we find that the Notch ligands suppress myeloid differentiation of progenitor cells and enhance expression of Notch target genes. By contrast, fucosylation-deficient myeloid progenitors are insensitive to the suppressive effects of Notch ligands on myelopoiesis, do not transcribe Notch1 target genes when cocultured with Notch ligands, and have lost the wild-type Notch ligand-binding phenotype. Considered together, these observations indicate that Notch-dependent signaling controls myelopoiesis in vivo and in vitro and identifies a requirement for Notch fucosylation in the expression of Notch ligand binding activity and Notch signaling efficiency in myeloid progenitors.

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Sturla, Laura, Raajit Rampal, Robert S. Haltiwanger, Floriana Fruscione, Amos Etzioni, and Michela Tonetti. "Differential Terminal Fucosylation ofN-Linked GlycansVersusProteinO-Fucosylation in Leukocyte Adhesion Deficiency Type II (CDG IIc)." Journal of Biological Chemistry 278, no. 29 (May 8, 2003): 26727–33. http://dx.doi.org/10.1074/jbc.m304068200.

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Li, Jun, Hui-Chen Hsu, Ping-Ar Yang, Qi Wu, and John Mountz. "Fucosylation regulates cell death in rheumatoid arthritis (87.24)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 87.24. http://dx.doi.org/10.4049/jimmunol.184.supp.87.24.

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Abstract Abnormal inflammation and apoptosis are major pathogenic features of synovial fibroblasts (SF) in rheumatoid arthritis (RA). Fucosylation, an important type of glycosylation, has been identified in cancer and inflammation conditions. The role of fucosylation in RA was investigated. Real-time PCR indicated that between RASF and osteoarthritis (OA) SF (N=14 each), there was no difference in the expression of apoptosis related molecules, including tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), its receptors DR4, DR5, DR6, DcR1, DcR2, and regulators of apoptosis FLIPL and cIAPs. However, there was a higher level of α1-2-Fucosyltransferase (Fut1, P=0.016), α1-3/1-4-Fucosyltransferase (Fut3, P=0.018) and α1-3-Fucosyltransferase (Fut6, P=0.038), but not α1-6-Fucosyltransferase (Fut8, P=0.910) in RA compared to OA synovial tissues. Interestingly, a strong positive correlation between TNFα and Fut1, Fut3 and Fut6 was identified. Fut1 also correlated with Il17a. Preincubation of RASFs with 2-Deoxy-D-Galactose (15 mM/ml), a FUT1 inhibitor, decreased the sensitivity to TRA-8, an anti-human DR5 antibody, mediated apoptosis and this effect can be reversed by fucose (15 mM). Similar results were also found on human monocyte/macrophage cell lines, HL60 and THP-1. Our studies suggest that fucosylation is strongly associated with abnormal inflammation and apoptosis in RA effector cells. Fucosylation might be a novel target for RA therapy.

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Olewicz-Gawlik, Anna, Izabela Korczowska-Łącka, and Paweł Hrycaj. "Soluble selectins and highly fucosylated ?1-antichymotrypsin in rheumatoid arthritis patients." Journal of Medical Science 84, no. 1 (March 30, 2015): 34–40. http://dx.doi.org/10.20883/medical.e33.

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Introduction. Fucosylation of acute phase proteins and serum soluble selectin levels is increased in rheumatoid arthritis (RA) patients and can influence leukocyte extravasation. Aim. The aim of this study was to evaluate the concentration and fucosylation of ?1-antichymotrypsin (ACT) in relation to serum concentrations of soluble forms of selectins in RA patients. Material and methods. Serum samples of 70 RA patients and 30 healthy controls were examined using sandwich enzyme-linked immunosorbent assay (ELISA). Results. ACT-FR was significantly increased in RA patients when compared to healthy controls (p < 0.001) and significantly correlated with serum concentrations of rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (ACPA) (p = 0.006, p = 0.04, respectively). Moreover, we found significant correlations between the serum levels of soluble (s)P- and sE-selectin and ACT-FR (p = 0.008 and p = 0.03, respectively) only in male RA patients.Conclusions. Fucosylation of ACT differs between male and female RA patients and is related to sP- and sE-selectin levels only in men.

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Martin, Tiphaine C., Mirna Šimurina, Marta Ząbczyńska, Marina Martinic Kavur, Magdalena Rydlewska, Marija Pezer, Kamila Kozłowska, et al. "Decreased Immunoglobulin G Core Fucosylation, A Player in Antibody-dependent Cell-mediated Cytotoxicity, is Associated with Autoimmune Thyroid Diseases." Molecular & Cellular Proteomics 19, no. 5 (February 5, 2020): 774–92. http://dx.doi.org/10.1074/mcp.ra119.001860.

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Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.

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Huang, Guoling, Zhi Li, Yuqing Li, Gang Liu, Shijie Sun, Jianguo Gu, Akihiko Kameyama, Wenzhe Li, and Weijie Dong. "Loss of core fucosylation in both ST6GAL1 and its substrate enhances glycoprotein sialylation in mice." Biochemical Journal 477, no. 6 (March 27, 2020): 1179–201. http://dx.doi.org/10.1042/bcj20190789.

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Fucosyltransferase 8 (FUT8) and β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) are glycosyltransferases that catalyze α1,6-fucosylation and α2,6-sialylation, respectively, in the mammalian N-glycosylation pathway. They are aberrantly expressed in various human diseases. FUT8 is non-glycosylated but is responsible for the fucosylation of ST6GAL1. However, the mechanism for the interaction between these two enzymes is unknown. In this study, we show that serum levels of α2,6-sialylated N-glycans are increased in Fut8−/− mice, whereas the mRNA and protein levels of ST6GAL1 are unchanged in mouse live tissues. The level of α2,6-sialylation on IgG was also enhanced in Fut8−/− mice along with ST6GAL1 catalytic activity increase in both serum and liver. Moreover, it was observed that ST6GAL1 prefers non-fucosylated substrates. Interestingly, increased core fucosylation accompanied by a reduction in α2,6-sialylation, was detected in rheumatoid arthritis patient serum. These findings provide new insight into the interactions between FUT8 and ST6GAL1.

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Robinson, Simon N., Hong Yang, William K. Decker, Dongxia Xing, David Steiner, Jingjing Ng, Michael W. Thomas, et al. "Fucosylation of Cord Blood CD34+ Cells Improves the Rate of Engraftment without Compromising Long-Term Engraftment." Blood 110, no. 11 (November 16, 2007): 1187. http://dx.doi.org/10.1182/blood.v110.11.1187.1187.

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Abstract INTRODUCTION: Delayed engraftment following cord blood (CB) transplantation remains a major challenge. While cell dose is clearly limiting, CB-derived hematopoietic stem cells (HSC) also appear to have a deficit in homing and engraftment. CB HSC have low levels of surface fucosylation. Increasing the level of surface fucosylation might improve interactions with selectins expressed by the microvasculature of the hematopoietic microenvironment, potentially improving homing and engraftment. METHODS: Human CB CD34+ were fucosylated using a recombinant fucosyltransferase (FTVI, Engraftin™, America Stem Cell, Inc., Carlsbad, CA) prior to injection into sublethally-irradiated NOD-SCID IL-2Rγnull mice. Levels of fucosylation were determined by flow cytometry using an anti-sialyl Lewis X antibody (a fucosylated selectin ligand). Each mouse received ∼4.5x104 CD34+ cells. The rate of engraftment was measured by the appearance of human CD45+ cells in the peripheral blood (PB). Following engraftment, multi-lineage reconstitution was measured (lymphoid, myeloid, platelet and erythroid). At termination (11 weeks post-transplant), levels of multi-lineage human engraftment were measured in PB, bone marrow (BM) and spleen. RESULTS: 1% of CD34+ cells in non-fucosylated samples were heavily fucosylated as compared to >90% in the FTVI-treated sample, confirming that significant de novo fucosylation of CD34+ cells had occurred.(Fig 1) Human engraftment was detected in mice receiving CD34+ cells treated with FTVI ∼2 weeks after transplant, and by ∼3 weeks had reached >1%. In mice receiving non-FTVI-treated CD34+ cells, 1% human engraftment was only realized >4 weeks after transplant. By this time human engraftment in the mice receiving FTVI-treated cells was 5-fold higher.(Fig 2) At 11 weeks post transplant, human engraftment was present in both groups in PB (10±1% vs. 4±1%), BM (33±1% vs. 43±1%) and spleen (42±1% vs. 31±2%). Further, in both groups, evidence of a similar pattern of multi-lineage engraftment was observed in PB, BM and spleen. CONCLUSION: These data suggest that increasing the levels of fucosylation of CB CD34+ cells using FTVI, dramatically improved the rate of engraftment, provided multi-lineage reconstitution and did not adversely effect long-term engraftment. This study supports further clinical development of fucosylation as a method of improving CB transplantation. Figure 1 Figure 1. Figure 2 Figure 2.

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Moriwaki, Kenta, and Eiji Miyoshi. "Roles of Fucosylation in Tumor Immunology." Trends in Glycoscience and Glycotechnology 22, no. 127 (2010): 239–46. http://dx.doi.org/10.4052/tigg.22.239.

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MILLETTE, CLARKE F., RICHARD A. CARDULLO, D. RANDALL ARMANT, and GEORGE L. GERTON. "Fucosylation Events during Mammalian Spermatogenesis b." Annals of the New York Academy of Sciences 513, no. 1 Cell Biology (December 1987): 58–73. http://dx.doi.org/10.1111/j.1749-6632.1987.tb24998.x.

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Perrin, Robyn M., Zhonghua Jia, Tanya A. Wagner, Malcolm A. O'Neill, Rodrigo Sarria, William S. York, Natasha V. Raikhel, and Kenneth Keegstra. "Analysis of Xyloglucan Fucosylation in Arabidopsis." Plant Physiology 132, no. 2 (April 24, 2003): 768–78. http://dx.doi.org/10.1104/pp.102.016642.

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Holdener, Bernadette C., and Robert S. Haltiwanger. "Protein O-fucosylation: structure and function." Current Opinion in Structural Biology 56 (June 2019): 78–86. http://dx.doi.org/10.1016/j.sbi.2018.12.005.

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Stoykova, L. I., R. L. Giuntoli, N. Rubinstei, and M. C. Glick. "S1.20 Control of membrane glycoprotein fucosylation." Glycoconjugate Journal 10, no. 4 (August 1993): 226. http://dx.doi.org/10.1007/bf01209821.

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Meng, Di, David S. Newburg, Cheryl Young, Amy Baker, Susan L. Tonkonogy, R. Balfour Sartor, W. Allan Walker, and N. Nanda Nanthakumar. "Bacterial symbionts induce a FUT2-dependent fucosylated niche on colonic epithelium via ERK and JNK signaling." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 4 (October 2007): G780—G787. http://dx.doi.org/10.1152/ajpgi.00010.2007.

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The intestinal epithelium of the adult gut supports a complex, dynamic microbial ecosystem and expresses highly fucosylated glycans on its surface. Uncolonized gut contains little fucosylated glycan. The transition toward adult colonization, such as during recovery from germ-free status or from antibiotic treatment, increased expression of fucosylated epitopes in the colonic epithelium. This increase in fucosylation is accompanied by induction of fut2 mRNA expression and α1,2/3-fucosyltransferase activity. Colonization stimulates ERK and JNK signal transduction pathways, resulting in activation of transcription factors ATF2 and c-Jun, respectively. This increases transcription of fut2 mRNA and expression of α1,2/3-fucosyltransferase activity, resulting in a highly fucosylated intestinal mucosa characteristic of the adult mammalian gut. Blocking the ERK and JNK signaling cascade inhibits the ability of colonization to induce elevated fut2 mRNA and fucosyltransferase activity in the mature colon. Thus pioneer-mutualist symbiotic bacteria may utilize the ERK and JNK signaling cascade to induce the high degree of fucosylation characteristic of adult mammalian colon, and we speculate that this fucosylation facilitates colonization by adult microbiota.

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IWAMORI, Masao, and Steven E. DOMINO. "Tissue-specific loss of fucosylated glycolipids in mice with targeted deletion of alpha(1,2)fucosyltransferase genes." Biochemical Journal 380, no. 1 (May 15, 2004): 75–81. http://dx.doi.org/10.1042/bj20031668.

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Glycolipids in epithelial tissues of the gastrointestinal tract act as receptors for enteric bacteria and are implicated in the activation of the intestinal immune system. To clarify the genes involved in the fucosylation of the major glycolipids, substrate glycolipids and fucosylated products were measured in tissues of wild-type and mutant mice lacking α(1,2)fucosyltransferase genes FUT1 or FUT2. Quantitative determination was performed by TLC-immunostaining for GA1 (Gg4Cer), FGA1 (fucosyl GA1), GM1 (II3NeuAc-Gg4Cer), FGM1 (fucosyl GM1), and Forssman glycolipids. Both FGM1 and FGA1 completely disappeared from the antrum, cecum, and colon of FUT2-null mice, but not those of FUT1-null and wild-type mice. Precursor glycolipids, GM1 and GA1, accumulated in tissues of FUT2-null mice, indicating that the FUT2-encoded enzyme preferentially participates in the fucosylation of GA1 and GM1 in these tissues. Female reproductive organs were similarly found to utilize FUT2 for the fucosylation of glycolipids FGA1 (uterus and cervix), and FGM1 (ovary), due to their absence in FUT2-null mice. In FUT1-null mice FGA1 was lost from the pancreas, but was present in wild-type and FUT2-null mice, indicating that FUT1 is essential for fucosylation of GA1 in the pancreas. Ulex europaeus agglutinin-I lectin histochemistry for α(1,2)fucose residues confirmed the absence of α(1,2)fucose residues from the apical surface of pancreatic acinar glands of FUT1-null mice. Ileum, epididymis, and testis retained specific fucosylated glycolipids, irrespective of targeted deletion of either gene, indicating either compensation for or redundancy of the α(1,2)fucosyltransferase genes in these tissues.

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Yu, Hai, Yanhong Li, Zhigang Wu, Lei Li, Jie Zeng, Chao Zhao, Yijing Wu, et al. "H. pylori α1–3/4-fucosyltransferase (Hp3/4FT)-catalyzed one-pot multienzyme (OPME) synthesis of Lewis antigens and human milk fucosides." Chemical Communications 53, no. 80 (2017): 11012–15. http://dx.doi.org/10.1039/c7cc05403c.

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Anokhina, E. P., M. M. Isuva, S. V. Startseva, E. A. Motina, N. A. Mihailova, and O. S. Korneeva. "INVESTIGATION OF PREBIOTIC, IMMUNOSTIMULATING PROPERTIES OF FUCOSE AND ITS EFFECT ON REPRODUCTIVE FUNCTION." Journal of microbiology epidemiology immunobiology, no. 6 (December 28, 2018): 110–14. http://dx.doi.org/10.36233/0372-9311-2018-6-110-114.

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Aim. Investigation of the effect of fucose in the diet on the gastrointestinal microflora of experimental animals with experimental dysbiosis, the humoral factors of nonspecific immunity, as well as the degree of fucosylation of oocytes and the proportion of oocytes that can be fertilized. Materials and methods. Prebiotic properties of fucose were studied by analyzing the luminal microflora of experimental mice against the background of experimental dysbiosis. Investigation of factors of nonspecific immunity was carried out after immunization of mice according to the level of antibody formation in blood serum by the method of enzyme immunoassay. The degree of fucosylation of oocytes was assessed by the intensity of their luminescence upon microscopy of oocytes of experimental mice on a fluorescent microscope. Results. The use of fucose in all tested doses led to the restoration of the composition and quantity of the gastrointestinal microflora. For the correction of dysbiosis, the optimal concentration of fucose was 0.02% of the body weight of the experimental animals. Inclusion of fucose in a diet of experimental animals in the amount of 0.008% to the body weight provided the highest level of immune response. The degree of fucosylation of oocytes, the proportion of oocytes capable of fertilization was increased when fucose were introduced in the amount of 0.008% to the body weight of the mice. Conclusion. Bifidogenic and lactogenic activity of fucose is established. The ability of fucose to stimulate an increase in the level of antibodies in in blood serum is shown. The tendency of positive effect of fucose in the diet of mice on the degree of fucosylation of oocytes was revealed.

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Tu, Mengjue, Xingshuo Fan, Jianan Shi, Shengnan Jing, Xiaole Xu, and Yuqin Wang. "2-Fluorofucose Attenuates Hydrogen Peroxide-Induced Oxidative Stress in HepG2 Cells via Nrf2/keap1 and NF-κB Signaling Pathways." Life 12, no. 3 (March 11, 2022): 406. http://dx.doi.org/10.3390/life12030406.

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Fucosylation is one of the most important glycan terminal modifications that affects multiple biological activities of proteins. 2-Fluorofucose (2FF), its specific inhibitor, has recently been reported to reveal numerous biological effects by blocking fucosylation both in vitro and in vivo. The current study aimed to evaluate the effect of 2FF on hydrogen peroxide (H2O2)-induced oxidative damage in vitro. In our study, treatment with H2O2 increased the level of fucosylation, and 2FF improved the cell viability in H2O2-treated HepG2 cells. Our study also showed that 2FF significantly decreased the overproduction of reactive oxygen species (ROS) induced by H2O2 and the activities of catalase, glutathione and Mn-superoxide dismutase were remarkably increased by 2FF pretreatment. Furthermore, 2FF attenuated H2O2-induced early mitochondria dysfunction. The second part of the study revealed that 2FF enhanced antioxidant capacity by affecting Nrf2/keap1 and NF-κB signaling pathways in HepG2 cells. Being pretreated with 2FF significantly increased the nuclear translocation of Nrf2 and simultaneously promoted the expression of downstream proteins, such as HO-1 and NQO1. Moreover, 2FF remarkably suppressed the expression of inflammation-associated proteins. Taken together, these data suggest that 2FF might have a potential therapeutic effect for oxidative stress.

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Verbij, Fabian, Eva Stokhuijzen, Floris van Alphen, Paul Kaijen, Alexander Meijer, and Jan Voorberg. "Analysis of the Glycan Composition on Plasma Derived ADAMTS13 Employing Tandem Mass Spectrometry." Blood 126, no. 23 (December 3, 2015): 1069. http://dx.doi.org/10.1182/blood.v126.23.1069.1069.

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Abstract Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder that results from the development of auto-antibodies against ADAMTS13 disrupting the binding of ADAMTS13 to von Willebrand factor and thereby preventing the proteinase activity and/or increasing the clearance from the circulation. Previous research from our department identified 9 O-linked glycosylation, 6 O-fucosylation and 2 C-mannosylation sites on plasma derived ADAMTS13. One of the N-linked glycosylation sites (N1354) is close to one of the previously identified peptides preferentially presented on HLA-DRB1*0301 and HLA-DRB1*1501 (ASYILIRD amino acid A1355-D1362) and also close to the HLA-DRB1*1101 peptide (FINVAPHAR amino acid F1328-R1336) suggesting a possible role for the glycosylation in the onset of acquired TTP. To study the glycosylation and glycan trees ADAMTS13 purified from cryosupernatant was reduced with dithiothreitol, alkylated with iodoacetamide and subsequently processed into peptides overnight with either trypsin or chymotrypsin. The peptides were then purified using ZIC-HILIC proteatips and finally analyzed by tandem mass spectrometry employing both higher-energy collision dissociation (HCD) and electron transfer dissociation (ETD). The data files were analyzed using the BYONIC software package as well as manually. Using this approach we identified the glycan structure on 10 N-linked glycosylation. Nine out of 10 glycans contained complex carbohydrate structures terminating in sialic acid. The glycans at these N-linked sites were identified both with or without a fucose on the primary GlcNAc. We were unable to identify a GalNAc residue in the glycan linked to N614 in the spacer domain. This suggest that the glycan on N614 consist primarily of high mannose structures. Binding of ADAMTS13 to the mannose receptor on dendritic cells is most likely facilitated by the high mannose glycan on N614. Furthermore we identified 6 O-linked glycosylation sites either on a serine of a threonine. One O-linked glycan is located in the spacer domain, 2 were found in the thrombospondin type 1 repeat-6 (TSP6), another one was found in TSP8 and 1 O-linked glycosylation site was found in both of the CUB domains. Four out of 6 O-glycans contained terminal sialic acid of which 2 also contained a fucose attached to the GlcNAc. Several O-glycans contained a terminal galactose residue; one O-glycan in TSP6 terminated in both a GlcNAc and a GalNAc residue. O-fucosylation is a common post-translational modification of thrombospondin type 1 repeats. We identified 9 O-fucosylation sites in the TSP repeats. Seven out of 9 sites adhered to the consensus sequence previously defined for O-fucosylation. TSP1 and 2 contained an additional O-fucosylation site at residues T407 and S724; these sites did not match the consensus sequence for O-fucosylation. Interestingly, two additional O-fucosylation sites were identified in cysteine rich and spacer domain at residue S553 and S698. All these residues were predicted to contain a glucose-fucose modification. Next to these glucose-fucose modifications we also identified 2 fucose modification in both of the CUB domains at residues S1170 and T1344. These results show that ADAMTS13 is extensively modified by O-fucosylation. Evidence for C-mannosylation of 8 different tryptophans was obtained. In accordance with previous findings the W387 or W390 (TSP1) and W884 (TSP4) were found to be C-mannosylated. We also found C-mannosylated tryptophans at position and W730 (TSP2) and W1081 (TSP8). Four additional C-mannosylated tryptophans were detected at position W208 (metallo proteinase domain), W1307 (CUB1 domain) and W1379 and W1406 (CUB2 domain). These results show that C-mannosylation is a common post translational modification in ADAMTS13 that is also found outside the TSP domains. Taken together these findings highlight the extensive post translational modification of ADAMTS13 by diverse carbohydrate structures. We anticipate that our findings might be relevant for the clearance and/or immune recognition of ADAMTS13. Disclosures No relevant conflicts of interest to declare.

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Calderon, Angie D., Lei Li, and Peng G. Wang. "FUT8: from biochemistry to synthesis of core-fucosylated N-glycans." Pure and Applied Chemistry 89, no. 7 (July 26, 2017): 911–20. http://dx.doi.org/10.1515/pac-2016-0923.

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AbstractGlycosylation is a major posttranslational modification of proteins. Modification in structure on N-glycans leads to many diseases. One of such modifications is core α-1,6 fucosylation, which is only found in eukaryotes. For this reason, lots of research has been done on approaches to synthesize core-fucosylated N-glycans both chemically and enzymatically, in order to have well defined structures that can be used as probes for glycan analysis and identifying functions of glycan-binding proteins. This review will focus on FUT8, the enzyme responsible for core fucosylation in mammals and the strategies that have been developed for the synthesis of core fucosylated N-glycans have been synthesized so far.

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Donald, Lynda J., Maureen Spearman, Neha Mishra, Emy Komatsu, Michael Butler, and Hélène Perreault. "Mass spectrometric analysis of core fucosylation and sequence variation in a human–camelid monoclonal antibody." Molecular Omics 16, no. 3 (2020): 221–30. http://dx.doi.org/10.1039/c9mo00168a.

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Zhao, Chao, Yijing Wu, Hai Yu, Ishita M. Shah, Yanhong Li, Jie Zeng, Bin Liu, David A. Mills, and Xi Chen. "The one-pot multienzyme (OPME) synthesis of human blood group H antigens and a human milk oligosaccharide (HMOS) with highly active Thermosynechococcus elongatus α1–2-fucosyltransferase." Chemical Communications 52, no. 20 (2016): 3899–902. http://dx.doi.org/10.1039/c5cc10646j.

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Chandler, Kevin Brown, Khalid A. Alamoud, Vanessa L. Stahl, Bach-Cuc Nguyen, Vinay K. Kartha, Manish V. Bais, Kenichi Nomoto, et al. "β-Catenin/CBP inhibition alters epidermal growth factor receptor fucosylation status in oral squamous cell carcinoma." Molecular Omics 16, no. 3 (2020): 195–209. http://dx.doi.org/10.1039/d0mo00009d.

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Journal articles on the topic 'Fucosylation'

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