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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 -
Nature Communications May 2021Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets....
Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.
Topics: Animals; B7 Antigens; Cell Line, Tumor; Female; Fucose; Fucosyltransferases; Gene Knockout Techniques; Glycosylation; HEK293 Cells; Humans; Immunity; Kaplan-Meier Estimate; Mice, Inbred BALB C; Mice, SCID; Polysaccharides; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays; Mice
PubMed: 33976130
DOI: 10.1038/s41467-021-22618-x -
Journal of Biomedical Science Mar 2021Previous study disclosed Fucosyltransferase 2 (Fut2) gene as a IBD risk locus. This study aimed to explore the mechanism of Fut2 in IBD susceptibility and to propose a...
BACKGROUND AND AIMS
Previous study disclosed Fucosyltransferase 2 (Fut2) gene as a IBD risk locus. This study aimed to explore the mechanism of Fut2 in IBD susceptibility and to propose a new strategy for the treatment of IBD.
METHODS
Intestinal epithelium-specific Fut2 knockout (Fut2) mice was used. Colitis was induced by dextran sulfate sodium (DSS). The composition and diversity of gut microbiota were assessed via 16S rRNA analysis and the metabolomic findings was obtained from mice feces via metabolite profiling. The fecal microbiota transplantation (FMT) experiment was performed to confirm the association of gut microbiota and LPC. WT mice were treated with Lysophosphatidylcholine (LPC) to verify its impact on colitis.
RESULTS
The expression of Fut2 and α-1,2-fucosylation in colonic tissues were decreased in patients with UC (UC vs. control, P = 0.036) and CD (CD vs. control, P = 0.031). When treated with DSS, in comparison to WT mice, more severe intestinal inflammation and destructive barrier functions in Fut2 mice was noted. Lower gut microbiota diversity was observed in Fut2 mice compared with WT mice (p < 0.001). When exposed to DSS, gut bacterial diversity and composition altered obviously in Fut2 mice and the fecal concentration of LPC was increased. FMT experiment revealed that mice received the fecal microbiota from Fut2 mice exhibited more severe colitis and higher fecal LPC concentration. Correlation analysis showed that the concentration of LPC was positively correlated with four bacteria-Escherichia, Bilophila, Enterorhabdus and Gordonibacter. Furthermore, LPC was proved to promote the release of pro-inflammatory cytokines and damage epithelial barrier in vitro and in vivo.
CONCLUSION
Fut2 and α-1,2-fucosylation in colon were decreased not only in CD but also in UC patients. Gut microbiota in Fut2 mice is altered structurally and functionally, promoting generation of LPC which was proved to promote inflammation and damage epithelial barrier.
Topics: Animals; Bacteria; Colitis; Fucosyltransferases; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Lysophosphatidylcholines; Mice; Mice, Transgenic; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 33722220
DOI: 10.1186/s12929-021-00711-z -
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 -
Nature Communications Mar 2023SPINDLY (SPY) in Arabidopsis thaliana is a novel nucleocytoplasmic protein O-fucosyltransferase (POFUT), which regulates diverse developmental processes. Sequence...
SPINDLY (SPY) in Arabidopsis thaliana is a novel nucleocytoplasmic protein O-fucosyltransferase (POFUT), which regulates diverse developmental processes. Sequence analysis indicates that SPY is distinct from ER-localized POFUTs and contains N-terminal tetratricopeptide repeats (TPRs) and a C-terminal catalytic domain resembling the O-linked-N-acetylglucosamine (GlcNAc) transferases (OGTs). However, the structural feature that determines the distinct enzymatic selectivity of SPY remains unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of SPY and its complex with GDP-fucose, revealing distinct active-site features enabling GDP-fucose instead of UDP-GlcNAc binding. SPY forms an antiparallel dimer instead of the X-shaped dimer in human OGT, and its catalytic domain interconverts among multiple conformations. Analysis of mass spectrometry, co-IP, fucosylation activity, and cryo-EM data further demonstrates that the N-terminal disordered peptide in SPY contains trans auto-fucosylation sites and inhibits the POFUT activity, whereas TPRs 1-5 dynamically regulate SPY activity by interfering with protein substrate binding.
Topics: Arabidopsis; Arabidopsis Proteins; Cryoelectron Microscopy; Fucose; Fucosyltransferases; Repressor Proteins
PubMed: 36941311
DOI: 10.1038/s41467-023-37279-1 -
Proceedings of the National Academy of... Jan 2022Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth...
Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2 Paneth cells were localized in the duodenum, whereas the majority of Fut2 Paneth cells were in the ileum. Fut2 Paneth cells showed higher granularity and structural complexity than did Fut2 Paneth cells, suggesting that Fut2 Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2 Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2 Paneth cells as part of gut defense.
Topics: Animals; Cytokines; Fucosyltransferases; Gastrointestinal Microbiome; Ileum; Interleukin-17; Interleukins; Mice; Paneth Cells; Symbiosis; alpha-Defensins; Interleukin-22; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 35027453
DOI: 10.1073/pnas.2115230119 -
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 -
Cell Communication and Signaling : CCS Mar 2023Fucosyltransferase 2(FUT2) and its induced α-1,2 fucosylation is associated with cancer metastasis. However, the role of FUT2 in colorectal cancer (CRC) metastasis...
BACKGROUND
Fucosyltransferase 2(FUT2) and its induced α-1,2 fucosylation is associated with cancer metastasis. However, the role of FUT2 in colorectal cancer (CRC) metastasis remains unclear.
METHODS
The expression levels and clinical analyses of FUT2 were assessed in CRC samples. Migration and invasion assays, EMT detection, nude mice peritoneal dissemination models and intestinal specific FUT2 knockout mice (FUT2 mice) were used to investigate the effect of FUT2 on metastasis in colorectal cancer. Quantitative proteomics study of glycosylated protein, UEA enrichment, Co-immunoprecipitation identified the mediator of the invasive-inhibiting effects of FUT2.
RESULTS
FUT2 is downregulated in CRC tissues and is positively correlated with the survival of CRC patients. FUT2 is an inhibitor of colorectal cancer metastasis which, when overexpressed, suppresses invasion and tumor dissemination in vitro and in vivo. FUT2 knock-out mice (FUT2 mice) develop AMO and DSS-induced tumors and promote EMT in colorectal cancers. FUT2-induced α-1,2 fucosylation impacts the ability of low-density lipoprotein receptor-related protein 1(LRP1) to suppress colorectal cancer invasion.
CONCLUSIONS
Our study demonstrated that FUT2 induces α-1,2 fucosylation and inhibits EMT and metastasis of colorectal cancer through LRP1 fucosylation, suggesting that FUT2 may serve as a therapeutic target for colorectal cancer. Video Abstract.
Topics: Animals; Mice; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Low Density Lipoprotein Receptor-Related Protein-1; Mice, Nude; Neoplasm Metastasis; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 36973740
DOI: 10.1186/s12964-023-01060-0 -
International Journal of Molecular... Aug 2022To investigate the effect of fucosyltransferase (FUT) 1-mediated fucosylation on meibomian glands (MG), we first confirmed that FUT1 and its fucosylated products were...
To investigate the effect of fucosyltransferase (FUT) 1-mediated fucosylation on meibomian glands (MG), we first confirmed that FUT1 and its fucosylated products were expressed in the eyelid, conjunctiva and skin in wild-type (WT) mice, whereas their mRNA and protein levels were downregulated in Fut1 knock-out (KO) mice. We then evaluated age-dependent changes in the total and acinar areas of MG, meibocyte differentiation, lipid synthesis, and eyelid inflammation and oxidative stress in Fut1 KO and WT mice. Results show that both the total and acinar areas of MG were smaller in Fut1 KO mice than in WT mice in all evaluated age groups. Meibocyte differentiation, lipid-producing capacities and the enzyme levels responsible for lipid synthesis were reduced in Fut1 KO mice, compared to WT controls. The levels of pro-inflammatory cytokines and oxidative-stress-related markers were elevated in the eyelids and MG of FUT1 KO mice. These findings demonstrate the physiologic function of FUT1-mediated fucosylation in MG development and function, and indicate its potential role in ocular surface homeostasis.
Topics: Animals; Fucosyltransferases; Lipids; Meibomian Glands; Mice; Mice, Knockout; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 36012728
DOI: 10.3390/ijms23169464 -
Acta Crystallographica. Section F,... Aug 2018Protein O-fucosylation is an important post-translational modification (PTM) found in cysteine-rich repeats in proteins. Protein O-fucosyltransferases 1 and 2 (PoFUT1... (Review)
Review
Protein O-fucosylation is an important post-translational modification (PTM) found in cysteine-rich repeats in proteins. Protein O-fucosyltransferases 1 and 2 (PoFUT1 and PoFUT2) are the enzymes responsible for this PTM and selectively glycosylate specific residues in epidermal growth factor-like (EGF) repeats and thrombospondin type I repeats (TSRs), respectively. Within the past six years, crystal structures of both enzymes have been reported, revealing important information on how they recognize protein substrates and achieve catalysis. Here, the structural information available today is summarized and how PoFUT1 and PoFUT2 employ different catalytic mechanisms is discussed.
Topics: Animals; Fucosyltransferases; Humans; Protein Structure, Secondary; Protein Structure, Tertiary; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 30084393
DOI: 10.1107/S2053230X18004788