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International Journal of Molecular... Jan 2021Aberrant glycosylation is a universal feature of cancer cells that can impact all steps in tumour progression from malignant transformation to metastasis and immune... (Review)
Review
Aberrant glycosylation is a universal feature of cancer cells that can impact all steps in tumour progression from malignant transformation to metastasis and immune evasion. One key change in tumour glycosylation is altered core fucosylation. Core fucosylation is driven by fucosyltransferase 8 (FUT8), which catalyses the addition of α1,6-fucose to the innermost GlcNAc residue of N-glycans. FUT8 is frequently upregulated in cancer, and plays a critical role in immune evasion, antibody-dependent cellular cytotoxicity (ADCC), and the regulation of TGF-β, EGF, α3β1 integrin and E-Cadherin. Here, we summarise the role of FUT8 in various cancers (including lung, liver, colorectal, ovarian, prostate, breast, melanoma, thyroid, and pancreatic), discuss the potential mechanisms involved, and outline opportunities to exploit FUT8 as a critical factor in cancer therapeutics in the future.
Topics: Animals; Fucose; Fucosyltransferases; Glycosylation; Humans; Neoplasms; Polysaccharides
PubMed: 33466384
DOI: 10.3390/ijms22010455 -
Gut Microbes 2023Intestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites...
Intestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites on ISCs stemness remain elusive. Fucose has been demonstrated to mediate host-microbe interactions in the intestine. However, the association between fucose, gut bacteria, and ISCs stemness remains unclear. To investigate the effects of fucose on ISCs-mediated intestinal epithelial cells (IECs) development, we administered fucose to 4-week-old mice for 4 weeks. ISCs stemness, IECs proliferation, and differentiation were examined. Variations in gut microbes and metabolism were detected using 16S rDNA sequencing and metabolomic analysis. Fucose was added to the bacterial culture medium to further study its effects on metabolism. Crypts were isolated from the mouse ileum for organoids culture in vitro to evaluate the effects of metabolites and the underlying mechanism. The results showed that fucose accelerated ISCs proliferation and secretory lineage differentiation in mice, whereas antibiotics eliminated these effects. The composition and functions of gut bacteria were altered by fucose treatment, while significant increases in and propanoate metabolism were noted. Propionic acid and propionate have been shown to promote organoid development. Fucose fermentation increases the production of propionic acid in and enhances its ability to increase the stemness of ISCs. Moreover, ileal contents from fucose-treated mice promoted organoid development in a Gpr41/Gpr43-dependent manner. Fucose administration activates the Wnt signaling pathway in ISCs, and Wnt inhibitors suppress the effects of fucose. We conclude that fucose accelerates ISC-mediated intestinal epithelial development by promoting -related propanoate metabolism. These findings provide new insights into the promotion of gut homeostasis and the application potential of fucose as a prebiotic.
Topics: Mice; Animals; Propionates; Fucose; Akkermansia; Gastrointestinal Microbiome; Intestinal Mucosa; Cell Differentiation; Stem Cells
PubMed: 37424378
DOI: 10.1080/19490976.2023.2233149 -
Redox Biology Apr 2023The intestinal epithelial repair after injury is coordinated by intestinal stem cells (ISCs). Fucosylation catalyzed by fucosyltransferase 2 (FUT2) of the intestinal...
The intestinal epithelial repair after injury is coordinated by intestinal stem cells (ISCs). Fucosylation catalyzed by fucosyltransferase 2 (FUT2) of the intestinal epithelium is beneficial to mucosal healing but poorly defined is the influence on ISCs. The dextran sulfate sodium (DSS) and lipopolysaccharide (LPS) model were used to assess the role of FUT2 on ISCs after injury. The apoptosis, function, and stemness of ISCs were analyzed using intestinal organoids from WT and Fut2 (ISC-specific Fut2 knockout) mice incubated with LPS and fucose. N-glycoproteomics, UEA-1 chromatography, and site-directed mutagenesis were monitored to dissect the regulatory mechanism, identify the target fucosylated protein and the corresponding modification site. Fucose could alleviate intestinal epithelial damage via upregulating FUT2 and α-1,2-fucosylation of ISCs. Oxidative stress, mitochondrial dysfunction, and cell apoptosis were impeded by fucose. Meanwhile, fucose sustained the growth and proliferation capacity of intestinal organoids treated with LPS. Contrarily, FUT2 depletion in ISCs aggravated the epithelial damage and disrupted the growth and proliferation capacity of ISCs via escalating LPS-induced endoplasmic reticulum (ER) stress and initiating the IRE1/TRAF2/ASK1/JNK branch of unfolded protein response (UPR). Fucosylation of the chaperone protein HYOU1 at the N-glycosylation site of asparagine (Asn) 862 mediated by FUT2 was identified to facilitate ISCs survival and self-renewal, and improve ISCs resistance to ER stress and inflammatory injury. Our study highlights a fucosylation-dependent protective mechanism of ISCs against inflammation, which may provide a fascinating strategy for treating intestinal injury disorders.
Topics: Animals; Mice; Fucose; Glycosylation; Lipopolysaccharides; Mice, Knockout; Stem Cells; Unfolded Protein Response; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 36724577
DOI: 10.1016/j.redox.2023.102618 -
Current Opinion in Structural Biology Jun 2019Fucose is a common terminal modification on protein and lipid glycans. Fucose can also be directly linked to protein via an O-linkage to Serine or Threonine residues... (Review)
Review
Fucose is a common terminal modification on protein and lipid glycans. Fucose can also be directly linked to protein via an O-linkage to Serine or Threonine residues located within consensus sequences contained in Epidermal Growth Factor-like (EGF) repeats and Thrombospondin Type 1 Repeats (TSRs). In this context, fucose is added exclusively to properly folded EGF repeats and TSRs by Protein O-fucosyltransferases 1 and 2, respectively. In both cases, the O-linked fucose can also be elongated with other sugars. Here, we describe the biological importance of these O-fucose glycans and molecular mechanisms by which they affect the function of the proteins they modify. O-Fucosylation of EGF repeats modulates the Notch signaling pathway, while O-fucosylation of TSRs is predicted to influence secretion of targets including several extracellular proteases. Recent data show O-fucose glycans mediate their effects by participating in both intermolecular and intramolecular interactions.
Topics: Fucose; Glycoproteins; Glycosylation; Humans; Phenotype
PubMed: 30690220
DOI: 10.1016/j.sbi.2018.12.005 -
The FEBS Journal Jun 2022O-linked modification of nuclear and cytosolic proteins with monosaccharides is essential in all eukaryotes. While many aspects of this post-translational modification...
O-linked modification of nuclear and cytosolic proteins with monosaccharides is essential in all eukaryotes. While many aspects of this post-translational modification are highly conserved, there are striking differences between plants and the animal kingdom. In animals, dynamic cycling of O-GlcNAc is established by two essential single copy enzymes, the O-GlcNAc transferase OGT and O-GlcNAc hydrolase OGA. In contrast, plants balance O-GlcNAc with O-fucose modifications, catalyzed by the OGT SECRET AGENT (SEC) and the protein O-fucosyltransferase (POFUT) SPINDLY (SPY). However, specific glycoside hydrolases for either of the two modifications have not yet been identified. Nucleocytoplasmic O-glycosylation is still not very well understood in plants, even though a high number of proteins were found to be affected. One important open question is how specificity is established in a system where only two enzymes modify hundreds of proteins. Here, we discuss the possibility that O-GlcNAc- and O-fucose-binding proteins could introduce an additional flexible layer of regulation in O-glycosylation-mediated signaling pathways, with the potential of integrating internal or external signals.
Topics: Acetylglucosamine; Animals; Cell Nucleus; Fucose; Glycosylation; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Signal Transduction
PubMed: 34051053
DOI: 10.1111/febs.16038 -
International Journal of Molecular... Dec 2021Fucosylation is an oligosaccharide modification that plays an important role in immune response and malignancy, and specific fucosyltransferases (FUTs) catalyze the... (Review)
Review
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.
Topics: Fucose; Fucosyltransferases; Glycosylation; Humans; Neoplasm Proteins; Oligosaccharides; Urologic Neoplasms
PubMed: 34948129
DOI: 10.3390/ijms222413333 -
Glycobiology Jul 2017Fucose is a 6-deoxy hexose in the l-configuration found in a large variety of different organisms. In mammals, fucose is incorporated into N-glycans, O-glycans and... (Review)
Review
Fucose is a 6-deoxy hexose in the l-configuration found in a large variety of different organisms. In mammals, fucose is incorporated into N-glycans, O-glycans and glycolipids by 13 fucosyltransferases, all of which utilize the nucleotide-charged form, GDP-fucose, to modify targets. Three of the fucosyltransferases, FUT8, FUT12/POFUT1 and FUT13/POFUT2, are essential for proper development in mice. Fucose modifications have also been implicated in many other biological functions including immunity and cancer. Congenital mutations of a Golgi apparatus localized GDP-fucose transporter causes leukocyte adhesion deficiency type II, which results in severe developmental and immune deficiencies, highlighting the important role fucose plays in these processes. Additionally, changes in levels of fucosylated proteins have proven as useful tools for determining cancer diagnosis and prognosis. Chemically modified fucose analogs can be used to alter many of these fucose dependent processes or as tools to better understand them. In this review, we summarize the known roles of fucose in mammalian physiology and pathophysiology. Additionally, we discuss recent therapeutic advances for cancer and other diseases that are a direct result of our improved understanding of the role that fucose plays in these systems.
Topics: Animals; Fucose; Fucosyltransferases; Humans; Immune System Diseases; Metabolic Diseases; Mutation; Neoplasms; Protein Processing, Post-Translational
PubMed: 28430973
DOI: 10.1093/glycob/cwx034 -
Parasitology Dec 2019Many invertebrates are either parasites themselves or vectors involved in parasite transmission; thereby, the interactions of parasites with final or intermediate hosts... (Comparative Study)
Comparative Study Review
Many invertebrates are either parasites themselves or vectors involved in parasite transmission; thereby, the interactions of parasites with final or intermediate hosts are often mediated by glycans. Therefore, it is of interest to compare the glycan structures or motifs present across invertebrate species. While a typical vertebrate modification such as sialic acid is rare in lower animals, antennal and core modifications of N-glycans are highly varied and range from core fucose, galactosylated fucose, fucosylated galactose, methyl groups, glucuronic acid and sulphate through to addition of zwitterionic moieties (phosphorylcholine, phosphoethanolamine and aminoethylphosphonate). Only in some cases are the enzymatic bases and the biological function of these modifications known. We are indeed still in the phase of discovering invertebrate glycomes primarily using mass spectrometry, but molecular biology and microarraying techniques are complementary to the determination of novel glycan structures and their functions.
Topics: Animals; Fucose; Glycosylation; Host-Parasite Interactions; Invertebrates; Polysaccharides; Sialic Acids; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 31046847
DOI: 10.1017/S0031182019000398 -
Molecular Carcinogenesis May 2022l-fucose is a dietary sugar that is used by cells in a process called fucosylation to posttranslationally modify and regulate protein behavior and function. As... (Review)
Review
l-fucose is a dietary sugar that is used by cells in a process called fucosylation to posttranslationally modify and regulate protein behavior and function. As fucosylation plays essential cellular functions in normal organ and immune developmental and homeostasis, it is perhaps not surprising that it has been found to be perturbed in a number of pathophysiological contexts, including cancer. Increasing studies over the years have highlighted key roles that altered fucosylation can play in cancer cell-intrinsic as well as paracrine signaling and interactions. In particular, studies have demonstrated that fucosylation impact tumor:immunological interactions and significantly enhance or attenuate antitumor immunity. Importantly, fucosylation appears to be a posttranslational modification that can be therapeutically targeted, as manipulating the molecular underpinnings of fucosylation has been shown to be sufficient to impair or block tumor progression and to modulate antitumor immunity. Moreover, the fucosylation of anticancer agents, such as therapeutic antibodies, has been shown to critically impact their efficacy. In this review, we summarize the underappreciated roles that fucosylation plays in cancer and immune cells, as well as the fucosylation of therapeutic antibodies or the manipulation of fucosylation and their implications as new therapeutic modalities for cancer.
Topics: Fucose; Glycosylation; Humans; Immunotherapy; Neoplasms; Sugars
PubMed: 35107186
DOI: 10.1002/mc.23394 -
International Journal of Molecular... Nov 2021The modification of sperm glycocalyx is an essential process during sperm capacitation. The presence and redistribution of terminal and linked fucose have been described...
The modification of sperm glycocalyx is an essential process during sperm capacitation. The presence and redistribution of terminal and linked fucose have been described during in vitro capacitation in humans. However, the influence of the capacitation time on the quantification and localization of terminal and linked fucose is still unknown. In this study, the quantitative and qualitative changes in fucosyl residues during different in vitro capacitation times (1 and 4 h), are simultaneously characterized by using (AAA) lectin-gold labelling and high-resolution field emission scanning electron microscopy (FE-SEM) in human sperm. A significant decrease was found in the number of terminal fucose registered in the whole sperm head during the in vitro capacitation. Nevertheless, the quantification of fucose residues after 1 h of in vitro capacitation was very similar to those found after 4 h. Therefore, the changes observed in terminal and linked fucose during capacitation were not time-dependent. Furthermore, the comprehensive analysis of the topographic distribution showed the preferential fucosyl location in the acrosomal region and the presence of distinct clusters distributed over the head in all the studied conditions. Overall, these findings corroborate the validity of FE-SEM combined with gold labelling to register changes in surface molecules during in vitro sperm capacitation.
Topics: Fucose; Glycocalyx; Humans; Lectins; Male; Microscopy, Electron, Scanning; Sperm Capacitation; Spermatozoa
PubMed: 34769375
DOI: 10.3390/ijms222111947