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Eiji Miyoshi - One of the best experts on this subject based on the ideXlab platform.
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Roles of Fucosyltransferases in Cancer Phenotypes
Glycosignals in Cancer: Mechanisms of Malignant Phenotypes, 2016Co-Authors: Eiji Miyoshi, Naofumi Uozumi, Tomoaki Sobajima, Shinji Takamatsu, Yoshihiro KamadaAbstract:Fucosylation is one of the most important types of glycosylation in carcinogenesis. Fucosylation is linked to certain processes in cell-cell interaction and dynamic regulation of growth factor receptor signaling on cell surface, and changes in Fucosylation result in differences of biological phenotype in cancer cells. Eleven fucosyltransferases are involved in the synthesis of fucosylated glycans and belong to some family of fucosyltransferases. To regulate cellular Fucosylation, GDP-fucose, a donor substrate of fucosyltransferases, and GDP-fucose transporter are also important. Terminal Fucosylation (Lewis-type Fucosylation) is associated with the synthesis of sialyl Lewis antigens, leading to cancer metastasis. In contrast, core Fucosylation is linked to the regulation of membrane-anchored glycoproteins, such as growth factor receptors and adhesion molecules. Target glycoproteins for each fucosyltransferase might be different in various kinds of cancer. In this chapter, we describe the roles of fucosyltransferase in several kinds of cancer, particularly gastroenterological cancers.
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Fucosylation is a common glycosylation type in pancreatic cancer stem cell-like phenotypes
World journal of gastroenterology, 2015Co-Authors: Naoko Terao, Tomoaki Sobajima, Shinji Takamatsu, Yoshihiro Kamada, Tomomi Minehira, Kotarosumitomo Nakayama, Eiji MiyoshiAbstract:AIM: To evaluate/isolate cancer stem cells (CSCs) from tissue or cell lines according to various definitions and cell surface markers. METHODS: Lectin microarray analysis was conducted on CSC-like fractions of the human pancreatic cancer cell line Panc1 by establishing anti-cancer drug-resistant cells. Changes in glycan structure of CSC-like cells were also investigated in sphere-forming cells as well as in CSC fractions obtained from overexpression of CD24 and CD44. RESULTS: Several types of Fucosylation were increased under these conditions, and the expression of Fucosylation regulatory genes such as fucosyltransferases, GDP-fucose synthetic enzymes, and GDP-fucose transporters were dramatically enhanced in CSC-like cells. These changes were significant in gemcitabine-resistant cells and sphere cells of a human pancreatic cancer cell line, Panc1. However, downregulation of cellular Fucosylation by knockdown of the GDP-fucose transporter did not alter gemcitabine resistance, indicating that increased cellular Fucosylation is a result of CSC-like transformation. CONCLUSION: Fucosylation might be a biomarker of CSC-like cells in pancreatic cancer.
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Fucosylation is a promising target for cancer diagnosis and therapy.
Biomolecules, 2012Co-Authors: Eiji Miyoshi, Kenta Moriwaki, Shinichiro Shinzaki, Tsutomu Nakagawa, Naoko Terao, Cheng-cheng Tan, Mika Terao, Hitoshi Matsumoto, Yoshihiro KamadaAbstract:Oligosaccharides, sequences of carbohydrates conjugated to proteins and lipids, are arguably the most abundant and structurally diverse class of molecules. Fucosylation is one of the most important oligosaccharide modifications involved in cancer and inflammation. Recent advances in glycomics have identified several types of glyco-biomarkers containing Fucosylation that are linked to certain types of cancer. Fucosylated alpha-fetoprotein (AFP) is widely used in the diagnosis of hepatocellular carcinoma because it is more specific than alpha-fetoprotein. High levels of fucosylated haptoglobin have also been found in sera of patients with various carcinomas. We have recently established a simple lectin-antibody ELISA to measure fucosylated haptoglobin and to investigate its clinical use. Cellular Fucosylation is dependent upon fucosyltransferase activity and the level of its donor substrate, guanosine diphosphate (GDP)-fucose. GDP-mannose-4,6-dehydratase (GMDS) is a key enzyme involved in the synthesis of GDP-fucose. Mutations of GMDS found in colon cancer cells induced a malignant phenotype, leading to rapid growth in athymic mice resistant to natural killer cells. This review describes the role of fucosylated haptoglobin as a cancer biomarker, and discusses the possible biological role of Fucosylation in cancer development.
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The effect of epigenetic regulation of Fucosylation on TRAIL-induced apoptosis
Glycoconjugate Journal, 2010Co-Authors: Kenta Moriwaki, Megumi Narisada, Taku Imai, Shinichiro Shinzaki, Eiji MiyoshiAbstract:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many cancer cells but not in normal ones. Recombinant TRAIL and agonistic antibodies to its cognate receptors are currently being studied as promising anticancer drugs. However, preclinical and clinical studies have shown that many types of human cancers are resistant to TRAIL agonists. We previously reported that a deficiency of Fucosylation, which is one of the most common oligosaccharide modifications, leads to resistance to TRAIL-induced apoptosis. In contrast, DNA methylation is associated with silencing of various tumor suppressor genes and resistance of cancer cells to anticancer drugs. The aim of this study is to clarify the involvement of DNA methylation in the regulation of cellular Fucosylation and the susceptibility to TRAIL-induced apoptosis. When nineteen cancer cell lines with relatively low Fucosylation levels were treated with a novel methyltransferase inhibitor, zebularine, an increase in the Fucosylation level was observed in many cancer cell lines. The expression of Fucosylation-related genes, such as the FX , GDP-fucose transporter , and Fut4 genes, was significantly increased after the treatment with zebularine. Moreover, a synergistic effect of zebularine on TRAIL-induced apoptosis was observed in several cancer cell lines, in which Fucosylation was increased by treatment with zebularine. This synergistic effect was independent of the expression of TRAIL receptors and caspase-8. These results indicate that cellular Fucosylation is regulated through DNA methylation in many cancer cells. Moreover, zebularine might be useful as a combination drug with TRAIL-based therapies in patients with TRAIL-resistant cancer.
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Fucosylation and gastrointestinal cancer.
World journal of hepatology, 2010Co-Authors: Kenta Moriwaki, Eiji MiyoshiAbstract:Fucose (6-deoxy-L-galactose) is a monosaccharide that is found on glycoproteins and glycolipids in verte-brates, invertebrates, plants, and bacteria. Fucosylation, which comprises the transfer of a fucose residue to oligosaccharides and proteins, is regulated by many kinds of molecules, including fucosyltransferases, GDP-fucose synthetic enzymes, and GDP-fucose transporter(s). Dramatic changes in the expression of fucosylated oligosaccharides have been observed in cancer and inflammation. Thus, monoclonal antibodies and lectins recognizing cancer-associated fucosylated oligosaccharides have been clinically used as tumor markers for the last few decades. Recent advanced glycomic approaches allow us to identify novel Fucosylation-related tumor markers. Moreover, a growing body of evidence supports the functional significance of Fucosylation at various pathophysiological steps of carcinogenesis and tumor progression. This review highlights the biological and medical significance of Fucosylation in gastrointestinal cancer.
Weidong Wang - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of core Fucosylation limits progression of diabetic kidney disease.
Biochemical and biophysical research communications, 2019Co-Authors: Ming Fang, Weidong Wang, Qingzhu Tang, Le Kang, Xiaolang Wang, Xianan Guo, Biaojie Qin, Hongli LinAbstract:Abstract Background FUT8-mediated core Fucosylation, which transfers a fucose residue from GDP-fucose to core-GlcNAc of the N-linked type glycoproteins, is crucial for signaling receptors function. Core Fucosylation is involved in various biological processes such as cell proliferation, apoptosis, differentiation and immune regulation. Our previous studies demonstrated that inhibiting core Fucosylation prevented renal interstitial fibrosis of UUO murine models, but its role in the development of diabetic kidney disease (DKD) remains unclear. This study aimed to clarify the protective effects and molecular mechanisms during the progress of DKD by inhibiting core Fucosylation in vivo. Methods Core Fucosylation was examined in streptozotocin (STZ)-induced diabetic mouse model. Then a new Fut8 mutation mouse model in which exon 7 of Fut8 gene is deleted was constructed for diabetes induction. Metabolic and renal parameters were measured. Renal structure, fibrosis, and podocyte injury were assessed, and underlying mechanisms were investigated. Results The levels of fasting blood glucose, glycated hemoglobin, kidney-weight-to- body-weight (KW/BW) and urine albumin-to-creatinine (ACR) were increased at 16 weeks post injection. KW/BW and urine ACR were decreased significantly by inhibiting core Fucosylation. The renal pathology, fibrosis, and podocyte injury were mitigated significantly by inhibiting core Fucosylation. The protective effects of inhibiting core Fucosylation were mediated by downregulated of the phosphorylation of Smad2/3 and extracellular signal-regulated kinase (ERK). Conclusions Our results indicate that FUT8-based treatment might be a promising intervention strategy in therapeutic paradigm of DKD.
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Inhibiting core Fucosylation attenuates glucose-induced peritoneal fibrosis in rats
Kidney international, 2018Co-Authors: Nan Shen, Nan Wang, Weidong Wang, Qingzhu Tang, Juan Jesus Carrero, Keping Wang, Yiyao DengAbstract:Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core Fucosylation, an important posttranslational modification of the TGF-β1 receptors, can regulate the activation of TGF-β1 signaling in renal interstitial fibrosis. However, it remains unclear whether core Fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core Fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core Fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-β1 and PDGF signaling pathways. Next the protective effects of blocking core Fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core Fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis.
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Novel Mechanism of the Pericyte-Myofibroblast Transition in Renal Interstitial Fibrosis: Core Fucosylation Regulation.
Scientific reports, 2017Co-Authors: Nan Wang, Nan Shen, Weidong Wang, Qingzhu Tang, Yiyao Deng, Anqi Liu, Zach OdehAbstract:Pericytes have been identified as a major source of myofibroblasts in renal interstitial fibrosis (RIF). The overactivation of several signaling pathways, mainly the TGF-β and PDGF pathways, initiates the pericyte-myofibroblast transition during RIF. Key receptors in these two pathways have been shown to be modified by fucosyltransferase 8 (FUT8), the enzyme that catalyzes core Fucosylation. This study postulated that core Fucosylation might play an important role in regulating the pericyte transition in RIF. The data showed that core Fucosylation increased with the extent of RIF in patients with IgA nephropathy (IgAN). Similarly, core Fucosylation of pericytes increased in both a unilateral ureteral occlusion (UUO) mouse model and an in vitro model of pericyte transition. Inhibition of core Fucosylation by adenoviral-mediated FUT8 shRNA in vivo and FUT8 siRNA in vitro significantly reduced pericyte transition and RIF. In addition, the activation of both the TGF-β/Smad and PDGF/ERK pathways was blocked by core Fucosylation inhibition. In conclusion, core Fucosylation may regulate the pericyte transition in RIF by modifying both the TGF-β/Smad and PDGF/ERK pathways. Glycosylation might be a novel "hub" target to prevent RIF.
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Inhibiting post-translational core Fucosylation prevents vascular calcification in the model of uremia.
The international journal of biochemistry & cell biology, 2016Co-Authors: Wen Xinyu, Nan Wang, Weidong Wang, Anqi Liu, Lingyu Wang, Mengying Zhou, Ming Fang, Hongli LinAbstract:Vascular calcification (VC) is an independent risk factor for cardiovascular disease and mortality in uremia. Post-translational core Fucosylation is implicated in a number of pathological processes. First, we investigated the role of core Fucosylation and key TGF-β1 pathway receptors in calcified arteries in vivo. To determine whether blocking core Fucosylation effectively inhibited VC and TGF-β/Smad signaling pathway, we established an in vitro model of phosphate-induced calcification in rat vascular smooth muscle cells (VSMCs) to assess the role of core Fucosylation in VC. Core fucose could be detected at markedly higher levels in calcified VSMCs than control cells. Fut8 (α-1,6 fucosyltransferase), the only enzyme responsible for core Fucosylation in humans, was significantly upregulated by high phosphate. Exposed to high phosphate media and blocking core Fucosylation in VSMCs by knocking down Fut8 using a siRNA markedly reduced calcium and phosphorus deposition and Cbfα1 expression (osteoblast-specific transcription factor), and increased α-Sma expression (smooth muscle cell marker). Fut8 siRNA significantly inhibited TGF-β/Smad2/3 signaling activation in VSMCs cultured in high phosphate media. In conclusion, this study provides evidence to suggest core Fucosylation plays a major role in the process of VC and appropriate blockade of core Fucosylation may represent a potential therapeutic strategy for treating VC in end-stage renal disease.
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Inhibition of TGF-β1-receptor posttranslational core Fucosylation attenuates rat renal interstitial fibrosis.
Kidney international, 2013Co-Authors: Nan Shen, Jianing Zhang, Weidong Wang, Hongli Lin, Dapeng Wang, Hua Xie, Zhe FengAbstract:The profibrotic cytokine transforming growth factor-β1 (TGF-β1) causes renal fibrosis by binding to receptors at the cell surface; however, it is not clear which of the TGF-β superfamily receptors correlates with renal fibrosis. To resolve this, we quantified TGF-β superfamily receptor expression in the kidneys of rats with unilateral ureteral obstruction using a real-time PCR gene array. Expression of activin receptor-like kinase (ALK)-5, ALK7, and TGF-β receptor II (TGF-βRII) mRNA increased significantly, while ALK6 mRNA expression was significantly decreased in the obstructed rat kidney. Core Fucosylation is essential for the proper function of both TGF-βRII and ALK5 in cultured human renal proximal tubular epithelial cells in vitro. Therefore, we targeted posttranslational core Fucosylation, regulated by α-1,6 fucosyltransferase (FUT8), by adenoviral-mediated knockdown of FUT8 mRNA in vivo and measured TGF-βRII and ALK5 expression and the progression of renal fibrosis. Despite long-term obstruction injury, inhibition of TGF-βRII and ALK5 of core Fucosylation ameliorated the progression of renal fibrosis, an effect independent of TGF-βRII and ALK5 expression. Thus, the regulation of TGF-β1-receptor core Fucosylation may provide a novel potential therapeutic strategy for treating renal fibrosis.
Naoyuki Taniguchi - One of the best experts on this subject based on the ideXlab platform.
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Core Fucosylation of N-linked Glycan for Fine-Tuning TGF-β Receptor Function
Glycoscience: Biology and Medicine, 2021Co-Authors: Xiangchun Wang, Naoyuki TaniguchiAbstract:Core Fucosylation of glycans regulate diverse biological functions through the modification of targeting proteins, such as TGF-β receptors, EGF receptor, integrin, VEGF receptor, and immunoglobulin mu heavy chain. In the TGF-β signaling transduction, fine-tuning of core Fucosylation of on TGF-β receptor amplified the biological effects of this pathway in the lung and kidney and neurite outgrowth. Significant alterations of pathology and physiology were observed in both animal and cell models.
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Core Fucosylation of the T Cell Receptor Is Required for T Cell Activation.
Frontiers in Immunology, 2018Co-Authors: Wei Liang, Jianguo Gu, Tonghui Ma, Jianing Zhang, Rui Yu, Zhi Li, Ming Li, Naoyuki TaniguchiAbstract:CD4+ T cell activation promotes the pathogenic process of systemic lupus erythematosus (SLE). T cell receptor (TCR) complex are highly core fucosylated glycoproteins, which play important roles in T cell activation. In the present study, we found that the core Fucosylation of CD4+ T cells was significantly increased in SLE patients. Loss of core fucosyltransferase (Fut8), the sole enzyme for catalyzing the core Fucosylation of N-glycan, significantly reduced CD4+ T cell activation and ameliorated the EAE-induced syndrome in Fut8-/- mice. T cell activation with OVA323-339 loaded major histocompatibility complex II (pMHC-II) on B cell was dramatically attenuated in Fut8-/-OT-II CD4+ T cells compared with Fut8+/+OT-II CD4+ T cells. Moreover, the phosphorylation of ZAP-70 was significantly reduced in Fut8+/+OT-II CD4+ T cells by the treatment of fucosidase. Our results suggest that core Fucosylation is required for efficient TCR-pMHC-II contacts in CD4+ T cell activation, and hyper core Fucosylation may serve as a potential novel biomarker in the sera from SLE patients.
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Core Fucosylation of the T Cell Receptor Is Required for T Cell Activation.
Frontiers in immunology, 2018Co-Authors: Wei Liang, Jianing Zhang, Shanshan Mao, Shijie Sun, Naoyuki TaniguchiAbstract:CD4+ T cell activation promotes the pathogenic process of systemic lupus erythematosus (SLE). T cell receptor (TCR) complex are highly core fucosylated glycoproteins, which play important roles in T cell activation. In this study, we found that the core Fucosylation of CD4+ T cells was significantly increased in SLE patients. Loss of core fucosyltransferase (Fut8), the sole enzyme for catalyzing the core Fucosylation of N-glycan, significantly reduced CD4+ T cell activation and ameliorated the experimental autoimmune encephalomyelitis-induced syndrome in Fut8-/- mice. T cell activation with OVA323-339 loaded major histocompatibility complex II (pMHC-II) on B cell was dramatically attenuated in Fut8-/-OT-II CD4+ T cells compared with Fut8+/+OT-II CD4+ T cells. Moreover, the phosphorylation of ZAP-70 was significantly reduced in Fut8+/+OT-II CD4+ T cells by the treatment of fucosidase. Our results suggest that core Fucosylation is required for efficient TCR-pMHC-II contacts in CD4+ T cell activation, and hyper core Fucosylation may serve as a potential novel biomarker in the sera from SLE patients.
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A high expression of GDP-fucose transporter in hepatocellular carcinoma is a key factor for increases in Fucosylation.
Glycobiology, 2007Co-Authors: Kenta Moriwaki, Naoyuki Taniguchi, Katsuhisa Noda, Takatoshi Nakagawa, Michio Asahi, Harumasa Yoshihara, Norio Hayashi, Eiji MiyoshiAbstract:Changes in the levels of Fucosylation regulate the biological phenotype of cancer cells and a specific Fucosylation, such as fucosylated α-fetoprotein (AFP-L3) has been clinically used as a tumor marker for hepatocellular carcinoma (HCC). However, detailed molecular mechanisms that explain the increased Fucosylation in HCC remain unknown despite 10 years of study by these researchers. Fucosylation is regulated by complicated mechanisms that involve several factors: fucosyltransferases, GDP-fucose transporter (GDP-Fuc Tr), and synthetic enzymes of GDP-fucose, such as GDP-mannose 4, 6-dehydratase (GMD), GDP-4-keto-6deoxy-mannose-3, 5-epimerase-4-reductase (FX), and GDPfucose pyrophosphorylase. In this study, the expression of Fucosylation-related genes in HCC tissues was studied and it was found that GDP-Fuc Tr is a key factor for increases in Fucosylation. A real-time reverse transcription polymerase chain reaction (RT-PCR) analysis showed significant increases in GDP-Fuc Tr and FX expression in HCC, and levels of the GMD protein were upregulated by posttranslational modification in HCC tissues. In vitro cell experiments showed that the level of GDP-Fuc Tr was the most significantly correlated with the level of cellular Fucosylation and the overexpression of GDP-Fuc Tr dramatically increased Fucosylation in Hep3B cells. The importance of GDP-Fuc Tr in the increase of Fucosylation was also confirmed with immunohistochemical analyses. These findings suggest that the upregulation of GDP-Fuc Tr plays a pivotal role in increased Fucosylation in HCC and represents an attractive target for new treatments and diagnosis for HCC.
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Deletion of Core Fucosylation on α3β1 Integrin Down-regulates Its Functions
The Journal of biological chemistry, 2006Co-Authors: Yanyang Zhao, Xiangchun Wang, Eiji Miyoshi, Satsuki Itoh, Tomoya Isaji, Yoshinobu Kariya, Kaoru Miyazaki, Nana Kawasaki, Naoyuki TaniguchiAbstract:The core Fucosylation (alpha1,6-Fucosylation) of glycoprotein is widely distributed in mammalian tissues. Recently alpha1,6-Fucosylation has been further reported to be very crucial by the study of alpha1,6-fucosyltransferase (Fut8)-knock-out mice, which shows the phenotype of emphysema-like changes in the lung and severe growth retardation. In this study, we extensively investigated the effect of core Fucosylation on alpha3beta1 integrin and found for the first time that Fut8 makes an important contribution to the functions of this integrin. The role of core Fucosylation in alpha3beta1 integrin-mediated events has been studied by using Fut8(+/+) and Fut8(-/-) embryonic fibroblasts, respectively. We found that the core Fucosylation of alpha3beta1 integrin, the major receptor for laminin 5, was abundant in Fut8(+/+) cells but was totally abolished in Fut8(-/-) cells, which was associated with the deficient migration mediated by alpha3beta1 integrin in Fut8(-/-) cells. Moreover integrin-mediated cell signaling was reduced in Fut8(-/-) cells. The reintroduction of Fut8 potentially restored laminin 5-induced migration and intracellular signaling. Collectively, these results suggested that core Fucosylation is essential for the functions of alpha3beta1 integrin.
Nan Shen - One of the best experts on this subject based on the ideXlab platform.
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Inhibiting core Fucosylation attenuates glucose-induced peritoneal fibrosis in rats
Kidney international, 2018Co-Authors: Nan Shen, Nan Wang, Weidong Wang, Qingzhu Tang, Juan Jesus Carrero, Keping Wang, Yiyao DengAbstract:Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core Fucosylation, an important posttranslational modification of the TGF-β1 receptors, can regulate the activation of TGF-β1 signaling in renal interstitial fibrosis. However, it remains unclear whether core Fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core Fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core Fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-β1 and PDGF signaling pathways. Next the protective effects of blocking core Fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core Fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis.
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Novel Mechanism of the Pericyte-Myofibroblast Transition in Renal Interstitial Fibrosis: Core Fucosylation Regulation.
Scientific reports, 2017Co-Authors: Nan Wang, Nan Shen, Weidong Wang, Qingzhu Tang, Yiyao Deng, Anqi Liu, Zach OdehAbstract:Pericytes have been identified as a major source of myofibroblasts in renal interstitial fibrosis (RIF). The overactivation of several signaling pathways, mainly the TGF-β and PDGF pathways, initiates the pericyte-myofibroblast transition during RIF. Key receptors in these two pathways have been shown to be modified by fucosyltransferase 8 (FUT8), the enzyme that catalyzes core Fucosylation. This study postulated that core Fucosylation might play an important role in regulating the pericyte transition in RIF. The data showed that core Fucosylation increased with the extent of RIF in patients with IgA nephropathy (IgAN). Similarly, core Fucosylation of pericytes increased in both a unilateral ureteral occlusion (UUO) mouse model and an in vitro model of pericyte transition. Inhibition of core Fucosylation by adenoviral-mediated FUT8 shRNA in vivo and FUT8 siRNA in vitro significantly reduced pericyte transition and RIF. In addition, the activation of both the TGF-β/Smad and PDGF/ERK pathways was blocked by core Fucosylation inhibition. In conclusion, core Fucosylation may regulate the pericyte transition in RIF by modifying both the TGF-β/Smad and PDGF/ERK pathways. Glycosylation might be a novel "hub" target to prevent RIF.
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Inhibition of TGF-β1-receptor posttranslational core Fucosylation attenuates rat renal interstitial fibrosis.
Kidney international, 2013Co-Authors: Nan Shen, Jianing Zhang, Weidong Wang, Hongli Lin, Dapeng Wang, Hua Xie, Zhe FengAbstract:The profibrotic cytokine transforming growth factor-β1 (TGF-β1) causes renal fibrosis by binding to receptors at the cell surface; however, it is not clear which of the TGF-β superfamily receptors correlates with renal fibrosis. To resolve this, we quantified TGF-β superfamily receptor expression in the kidneys of rats with unilateral ureteral obstruction using a real-time PCR gene array. Expression of activin receptor-like kinase (ALK)-5, ALK7, and TGF-β receptor II (TGF-βRII) mRNA increased significantly, while ALK6 mRNA expression was significantly decreased in the obstructed rat kidney. Core Fucosylation is essential for the proper function of both TGF-βRII and ALK5 in cultured human renal proximal tubular epithelial cells in vitro. Therefore, we targeted posttranslational core Fucosylation, regulated by α-1,6 fucosyltransferase (FUT8), by adenoviral-mediated knockdown of FUT8 mRNA in vivo and measured TGF-βRII and ALK5 expression and the progression of renal fibrosis. Despite long-term obstruction injury, inhibition of TGF-βRII and ALK5 of core Fucosylation ameliorated the progression of renal fibrosis, an effect independent of TGF-βRII and ALK5 expression. Thus, the regulation of TGF-β1-receptor core Fucosylation may provide a novel potential therapeutic strategy for treating renal fibrosis.
Adam W. Barb - One of the best experts on this subject based on the ideXlab platform.
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Antibody Fucosylation Lowers the FcγRIIIa/CD16a Affinity by Limiting the Conformations Sampled by the N162-Glycan
ACS chemical biology, 2018Co-Authors: Daniel J. Falconer, Ganesh P. Subedi, Aaron M. Marcella, Adam W. BarbAbstract:Therapeutic monoclonal antibodies (mAbs) are largely based on the immunoglobulin G1 (IgG1) scaffold, and many elicit a cytotoxic cell-mediated response by binding Fc γ receptors. Core Fucosylation, a prevalent modification to the asparagine (N)-linked carbohydrate on the IgG1 crystallizable fragment (Fc), decreases the Fc γ receptor IIIa (CD16a) binding affinity and mAb efficacy. We determined IgG1 Fc Fucosylation reduced the CD16a affinity by 1.7 ± 0.1 kcal/mol when compared to that of afucosylated IgG1 Fc; however, CD16a N-glycan truncation decreased this penalty by 1.2 ± 0.1 kcal/mol or 70%. Fc Fucosylation restricted the manifold of conformations sampled by displacing the CD16a Asn162-glycan that impinges upon the linkage between the α-mannose(1–6)β-mannose residues and promoted contacts with the IgG Tyr296 residue. Fucosylation also impacted the IgG1 Fc structure as indicated by changes in resonance frequencies and nuclear spin relaxation observed by solution nuclear magnetic resonance spectroscopy. ...
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antibody Fucosylation lowers the fcγriiia cd16a affinity by limiting the conformations sampled by the n162 glycan
ACS Chemical Biology, 2018Co-Authors: Daniel J. Falconer, Ganesh P. Subedi, Aaron M. Marcella, Adam W. BarbAbstract:Therapeutic monoclonal antibodies (mAbs) are largely based on the immunoglobulin G1 (IgG1) scaffold, and many elicit a cytotoxic cell-mediated response by binding Fc γ receptors. Core Fucosylation, a prevalent modification to the asparagine (N)-linked carbohydrate on the IgG1 crystallizable fragment (Fc), decreases the Fc γ receptor IIIa (CD16a) binding affinity and mAb efficacy. We determined IgG1 Fc Fucosylation reduced the CD16a affinity by 1.7 ± 0.1 kcal/mol when compared to that of afucosylated IgG1 Fc; however, CD16a N-glycan truncation decreased this penalty by 1.2 ± 0.1 kcal/mol or 70%. Fc Fucosylation restricted the manifold of conformations sampled by displacing the CD16a Asn162-glycan that impinges upon the linkage between the α-mannose(1–6)β-mannose residues and promoted contacts with the IgG Tyr296 residue. Fucosylation also impacted the IgG1 Fc structure as indicated by changes in resonance frequencies and nuclear spin relaxation observed by solution nuclear magnetic resonance spectroscopy. ...
