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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 Fut2 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.

Aberrant fucosylation is the hallmark of malignant cell transformation, leading to many cellular events, such as uncontrolled cell proliferation, angiogenesis, tumor cell invasion, and metastasis. This increased fucosylation is caused due to the over-expression of fucosyltransferases (FUTs) that catalyzes the transfer of the fucose (Fuc) residue from GDP-fucose (donor substrate) to various oligosaccharides, glycoproteins, and glycolipids (acceptor substrates). Hence, fucosyltransferases (FUTs) are considered as validated target for the drug discovery against on cancers. In the current study, a drug repurposing approach was deployed to identify new hits against fucosyltransferase 2 (FUT2), using computational and biophysical techniques. A library of 500 US-FDA approved drugs were screened in-silico against fucosyltransferase 2 (FUT2) donor and acceptor sites. Five drugs were predicted as hits, based on their significant docking scores (-5.8 to -8.2), and binding energies (-43 to -51.19 Kcal/mol). Furthermore, STD-NMR highlighted the epitope of these drugs in the binding site of fucosyltransferase 2 (FUT2). Simulation studies provided insights about the binding site of these drugs, and 4 of them, acarbose, ascorbic acid, ibuprofen, and enalaprilat dihydrate, were found as significant binders at the donor binding site of fucosyltransferase 2 (FUT2). Hence, the current study reports the repurposed drugs as potential hits against fucosyltransferase 2 (FUT2). These may be further studied through in-vitro and in-vivo inhibitory and mechanistic studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Atif et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: ABO blood group antigens (ABH antigens) are carbohydrate chains glycosylated on epithelial and red blood cells. Recent findings suggest reduced ABH expression in psoriasis and atopic dermatitis, a chronic inflammatory skin disease with retained scale. H antigen, a precursor for A and B antigens, is synthesized by fucosyltransferase 1 (FUT1). Desmosomes, critical for skin integrity, are known to require N-glycosylation for stability. We investigate the impact of H antigens, a specific type of glycosylation, on desmosomes in keratinocytes., Method: Primary human keratinocytes were transfected with FUT1 siRNA or recombinant adenovirus for FUT1 overexpression. Cell adhesion and desmosome characteristics and their underlying mechanisms were analyzed., Result: The knockdown of FUT1, responsible for H2 antigen expression in the skin, increased cell-cell adhesive strength and desmosome size in primary cultured keratinocytes without altering the overall desmosome structure. Desmosomal proteins, including desmogleins or plakophilin, were upregulated, suggesting enhanced desmosome assembly. Reduced H2 antigen expression via FUT1 knockdown led to increased keratinocyte differentiation, evidenced by elevated expression of differentiation markers. Epidermal growth factor receptor (EGFR) has been described to be associated with FUT1 and promotes cell migration and differentiation. The effects of FUT1 knockdown were recapitulated by an EGFR inhibitor concerning desmosomal proteins and cellular differentiation. Further investigation demonstrated that the FUT1 knockdown reduced EGFR signaling by lowering the levels of EGF ligands rather than directly regulating EGFR activity. Moreover, FUT1 overexpression reversed the effects observed in FUT1 knockdown, resulting in the downregulation of desmosomal proteins and differentiation markers while increasing both mRNA and protein levels of EGFR ligands., Conclusion: The expression level of FUT1 in the epidermis appears to influence cell-cell adhesion and keratinocyte differentiation status, at least partly through regulation of H2 antigen and EGFR ligand expression. These observations imply that the fucosylation of the H2 antigen by FUT1 could play a significant role in maintaining the molecular composition and regulation of desmosomes and suggest a possible involvement of the altered H2 antigen expression in skin diseases, such as psoriasis and atopic dermatitis., (© 2024. The Author(s).)

Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide because of its high rate of metastasis, and approximately 20% of CRC patients have metastases at initial diagnosis. Metabolic reprogramming, a hallmark of cancer cells, has been implicated in the process of metastasis. We previously demonstrated that fucosyltransferase 2 (FUT2) promotes the malignancy of CRC cells, however, the underlying mechanisms remain unclear. Here, bioinformatic analysis revealed that FUT2 is associated with the malignant phenotype and fatty acid metabolism in CRC. FUT2 knockdown decreased glucose uptake and de novo fatty acid synthesis, which in turn inhibited the proliferation and metastasis of CRC cells. Mechanistically, FUT2 promotes YAP1 nuclear translocation and stabilizes mSREBP-1 by fucosylation, thus promoting de novo fatty acid synthesis in CRC cells. In summary, this study demonstrates that FUT2 promotes the proliferation and metastasis of CRC cells by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1, indicating that FUT2 might be a potential target for developing therapeutic strategies against CRC., (© 2024. The Author(s).)

The embryonic cell surface is rich in glycosphingolipids (GSLs), which change during differentiation. The reasons for GSL subgroup variation during early embryogenesis remain elusive. By combining genomic approaches, flow cytometry, confocal imaging, and transcriptomic data analysis, we discovered that α1,2-fucosylated GSLs control the differentiation of human pluripotent cells (hPCs) into germ layer tissues. Overexpression of α1,2-fucosylated GSLs disrupts hPC differentiation into mesodermal lineage and reduces differentiation into cardiomyocytes. Conversely, reducing α1,2-fucosylated groups promotes hPC differentiation and mesoderm commitment in response to external signals. We find that bone morphogenetic protein 4 (BMP4), a mesodermal gene inducer, suppresses α1,2-fucosylated GSL expression. Overexpression of α1,2-fucosylated GSLs impairs SMAD activation despite BMP4 presence, suggesting α-fucosyl end groups as BMP pathway regulators. Additionally, the absence of α1,2-fucosylated GSLs in early/late mesoderm and primitive streak stages in mouse embryos aligns with the hPC results. Thus, α1,2-fucosylated GSLs may regulate early cell-fate decisions and embryo development by modulating cell signaling., (© 2024. The Author(s).)

Objective: Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms., Methods: Intestinal mucositis animal models were induced in mice for in vivo studies. Rat intestinal cell line IEC-6 was used for in vitro studies. RNA‑seq was used to explore the transcriptomic changes in doxorubicin-induced intestinal mucositis. Intact glycopeptide characterization using mass spectrometry was applied to identify α-1,2-fucosylated proteins associated with mucositis., Results: Doxorubicin treatment increased RIP3 expression in the intestine and caused severe intestinal mucositis in the mice, depletion of RIP3 abolished doxorubicin-induced intestinal mucositis. RIP3-mediated doxorubicin-induced mucositis did not depend on mixed lineage kinase domain-like (MLKL) but on α-1,2-fucosyltransferase 2 (FUT2)-catalyzed α-1,2-fucosylation on inflammation-related proteins. Deficiency of MLKL did not affect intestinal mucositis, whereas inhibition of α-1,2-fucosylation by 2-deoxy-D-galactose (2dGal) profoundly attenuated doxorubicin-induced inflammation and mucositis., Conclusions: RIP3-FUT2 pathway is a central node in doxorubicin-induced intestinal mucositis. Targeting intestinal RIP3 and/or FUT2-mediated α-1,2-fucosylation may provide potential targets for preventing chemotherapy-induced intestinal mucositis., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Glycans containing fucose play crucial roles in cell biology, particularly in recognition processes. In humans, fucose found in H-blood group antigens is recognized by various pathogens, thereby influencing host-pathogen interactions. However, in invertebrate biology the specific functions of these modifications and the corresponding glycosyltransferases are not fully elucidated. Therefore, cloning these glycosyltransferases from different model systems will provide valuable insights into this process. Little is known about fucosyltransferases in molluscs. For this study, a sequence of the Pacific oyster, Crassostrea gigas, based on amino acid sequence homologies with rabbit and human α-1,2-fucosyltransferases, was chosen. The recombinant enzyme (350 amino acids) was able to transfer fucose from GDP-fucose to the galactose residue of type II disaccharides, terminal galactoses in complex N-glycan structures and several linear and branched galactans which were tested using a glycan microarray. The α-1,2-linkage formed was confirmed by NMR analysis. The enzyme was active in a broad pH-range, it was relatively stable upon storage conditions and its activity was not dependent on the presence of divalent cations. In this study, we were able to clone, express and characterise a novel α-1,2-fucosyltrasferase from Crassostrea gigas (CgFUT2)., (© 2024. The Author(s).)

Background: Vitamin B12 deficiency is a recognised cause of neurological manifestations, including peripheral neuropathy, behavioural changes, and seizures. However, developmental and epileptic encephalopathy due to vitamin B12 deficiency is very rare. Here, we report an infant with vitamin B12-responsive developmental and epileptic encephalopathy due to a novel mutation in the fucosyltransferase 2 (FUT2) gene responsible for vitamin B12 absorption., Case Presentation: An 11-month-old girl of non-consanguineous parents presented with recurrent episodes of seizures since four months. Her seizures started as flexor epileptic spasms occurring in clusters resembling infantile epileptic spasms syndrome with hypsarrhythmia in the electroencephalogram. She was treated with multiple drugs, including high-dose prednisolone, vigabatrin, sodium valproate, levetiracetam and clobazam, without any response, and she continued to have seizures at 11 months. She had an early developmental delay with maximally achieving partial head control and responsive smile at four months. Her development regressed with the onset of seizure; at 11 months, her developmental age was below six weeks. On examination, she was pale and had generalised hypotonia with normal muscle power and reflexes. Her full blood count and blood picture revealed macrocytic anaemia with oval and round macrocytes. Bone marrow aspiration showed hypercellular marrow erythropoiesis with normoblastic and megaloblastic maturation. Due to the unusual association of refractory epilepsy and megaloblastic anaemia, a rare genetic disease of the vitamin B12 or folate pathways was suspected. The whole exome sequencing revealed a homozygous missense variant in exon 2 of the FUT2 gene associated with reduced vitamin B12 absorption and low plasma vitamin B12 levels, confirming the diagnosis of vitamin B12 deficiency related developmental and epileptic encephalopathy. She was started on intramuscular hydroxocobalamin, for which she showed a marked response with reduced seizure frequency., Conclusion: We report a novel variant in the FUT2 gene associated with vitamin B12-responsive developmental and epileptic encephalopathy and megaloblastic anaemia. This case report highlights the importance of timely genetic testing in children with refractory developmental and epileptic encephalopathy to identify treatable causes., (© 2024. The Author(s).)

Background: As is well documented, the para-Bombay phenotype is typically characterized by the reduction or absence of ABH antigens on red blood cells but the presence of corresponding antigens in saliva. Herein, the underlying molecular mechanism of an individual with para-Bombay AB phenotype combined with two novel variants of the FUT1 gene was investigated., Materials and Methods: ABH antigens and antibodies were detected in the serum of the proband using conventional serological methods. The coding region nucleotides of the ABO, FUT1, and FUT2 genes were directly sequenced by polymerase chain reaction. Moreover, the FUT1 haploid type in the proband was analyzed by TA clone sequencing. The 3D structure of wild-type and mutant fucosyltransferases were simulated and analyzed using Phyre2 and Pymol software. Lastly, the effect of missense substitution on the function of fucosyltransferase was predicted by the Polymorphism Phenotyping algorithm (PolyPhen-2) and MutationTaster., Results: ABH antigens were noted to be absent on the surface of red blood cells of the proband. The ABO genotype was ABO*A1.02/ABO*B.01, while the FUT2 genotype was FUT2*01/FUT2*c.357T. Interestingly, two novel missense variants (c.289G>A, p.Ala97Thr and c.575G>C, p.Arg192Pro) and one synonymous SNP (c.840G>A) were identified in the FUT1 gene. Furthermore, c.289G>A was detected in one haploid type, whereas c.575G>C and c.840G>A were discovered in another haploid type. Meanwhile, in silico analysis revealed that amino acid substitution caused by missense variants altered the partial spatial structure of the α-helices where residues 97 and 298 were located using 3D homology modeling software. Finally, both missense variants were defined as probably damaging based on PolyPhen-2 prediction., Discussion: Two novel FUT1 variants were identified in a Chinese individual with para-Bombay AB phenotype, which can expand our understanding of the molecular mechanism underlying the para-Bombay phenotype and contribute to improving the safety of blood transfusion.

Fucosyltransferase 2 (FUT2) gene, which regulates the formation of Histoblood group antigens, could determine the human susceptibility to norovirus. This study aimed to investigate the correlation between FUT2 gene polymorphism and susceptibility to norovirus gastroenteritis in Han Chinese population. A total of 212 children patients with acute gastroenteritis were enrolled. The stool and serum samples were collected respectively. We used the qPCR method to detect the norovirus infection status from the stool samples, and we used serum samples to detect the FUT2 polymorphism. A case-control study was conducted to investigate the three common SNPs polymorphisms (rs281377, rs1047781, and rs601338) of FUT2 gene with sanger sequencing method. The results indicated that the homozygous genotypes and mutant allele of rs1047781 (A385T) would downgrade the risk of norovirus gastroenteritis in Chinese Han population (AA vs. TT, odds ratio [OR] = 0.098, 95% confidence interval [CI] = 0.026-0.370, p = 0.001; AA + AT vs. TT, OR = 0.118. 95% CI = 0.033-0.424, p = 0.001; A vs. T, OR = 0.528, 95% CI = 0.351-0.974, p = 0.002). There were no significant difference of rs281377 (C357T) and rs601338 (G428A) polymorphisms between norovirus positive and norovirus negative groups (p > 0.05). The haplotype T-T-G was less susceptible (OR = 0.49, 95% CI = 0.31-0.79, p = 0.0034) to norovirus infection compared to other haplotypes. Our results investigated the relationship between the FUT2 gene polymorphisms and norovirus susceptibility in Han Chinese population, and firstly revealed that children with homozygous genotypes and mutant alleles of FUT2 rs1047781 (A385T) were less susceptible to norovirus gastroenteritis., (© 2024 Wiley Periodicals LLC.)

Purpose: Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance., Materials and Methods: Using a training/validation study design, FUT2 / FUT3 genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay., Results: In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] v 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUC PR ) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2., Conclusion: Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.

The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 levels in the body. Vitamin B12 deficiency associated with hyperhomocysteinemia is a major risk factor for cardiovascular diseases (CVDs), which are one of the main causes of death in patients after kidney transplantation. The aim of our study was to determine the impact of the rs602662 (G>A) polymorphism of the FUT2 gene on the functionality of transplanted kidneys and the risk of CVD in patients after kidney transplantation. The study included 402 patients treated with immunosuppression (183 patients taking cyclosporine (CsA) and 219 patients taking tacrolimus (TAC)). The analysis of the FUT2 rs602662 (G>A) polymorphism was performed using real-time PCR. Patients with CsA were more likely to be underweight (1.64% vs. 0.91%) and obese (27.87% vs. 15.98%), while those taking TAC were more likely to be of normal weight (39.27%) or overweight (43.84%). No statistically significant differences were observed comparing the mean blood pressure, both systolic and diastolic. The renal profile showed a higher median urea nitrogen concentration in patients with CsA (26.45 mg/dL (20.60-35.40) vs. 22.95 mg/dL (17.60-33.30), p = 0.004). The observed frequency of rs602662 alleles of the FUT2 gene was similar in the analyzed groups. The A allele was present in 43.7% of patients with CsA and 41.1% of those taking TAC (OR = 0.898; 95% CI: 0.678-1.189; p = 0.453). In the group with CsA, the GG genotype was present in 32.2% of patients, the GA in 48.1% and the AA in 19.7%. A similar distribution was obtained in the TAC group: GG-33.8%, GA-50.2%, and AA-16.0%. An association of genotypes containing the G allele with a higher incidence of hypertension was observed. The G allele was present in 65% of people with hypertension and in 56% of patients with normal blood pressure ( p = 0.036). Moreover, the evaluation of the renal parameters showed no effect of the FUT2 polymorphism on the risk of organ rejection because the levels of creatinine, eGFR, potassium, and urea nitrogen were prognostic of successful transplantation. Our results suggest that the rs6022662 FUT2 polymorphism may influence the risk of cardiovascular diseases.

Fucosyltransferase 2 (FUT2) is an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. The H antigen is an oligosaccharide moiety that acts as both an attachment site and carbon source for intestinal bacteria. Non-secretors, who are homozygous for the loss-of-function alleles of FUT2 gene (sese), have increased susceptibility to Crohn's disease (CD). To characterize the effect of FUT2 polymorphism on the mucosal ecosystem, we profiled the microbiome, meta-proteome and meta-metabolome of 75 endoscopic lavage samples from the cecum and sigmoid of 39 healthy subjects (12 SeSe, 18 Sese and 9 sese). Imputed metagenomic analysis revealed perturbations of energy metabolism in the microbiome of non-secretor and heterozygote individuals, notably the enrichment of carbohydrate and lipid metabolism, cofactor and vitamin metabolism and glycan biosynthesis and metabolism-related pathways, and the depletion of amino-acid biosynthesis and metabolism. Similar changes were observed in mice bearing the FUT2(-/-) genotype. Metabolomic analysis of human specimens revealed concordant as well as novel changes in the levels of several metabolites. Human metaproteomic analysis indicated that these functional changes were accompanied by sub-clinical levels of inflammation in the local intestinal mucosa. Therefore, the colonic microbiota of non-secretors is altered at both the compositional and functional levels, affecting the host mucosal state and potentially explaining the association of FUT2 genotype and CD susceptibility.

The presence of the blood group H2 antigen on the membrane of red blood cells determines blood type O in individuals and this H2 antigen serves as a precursor to the A and B antigens expressed in blood types A and B, respectively. However, the specific involvement of ABH antigens in skin diseases is unknown. Therefore, we aim to investigate the expression of ABH antigens in skin tissue of patients with atopic dermatitis (AD) and MC903-induced AD-like mice. We demonstrated that the expression of ABH antigen is primarily located in the granular and horny layers of the skin in healthy control individuals. However, in patients with AD, the expression of the ABH antigen was absent or diminished in these layers, while the H2 antigen expression increased in the spinous layers of the affected skin lesions. Then, we investigated the biological function of blood group H antigen mediated by fucosyltransferase 1 (Fut1) in the skin, utilizing an AD mouse model induced by MC903 in wild-type (WT) and Fut1 -knockout mice. After the application of MC903, Fut1-deficient mice, with no H2 antigen expression on their skin, exhibited more severe clinical signs, increased ear swelling, and elevated serum IgE levels compared with those of WT mice. Additionally, the MC903-induced thickening of both the epidermis and dermis was more pronounced in Fut1-deficient mice than that in WT mice. Furthermore, Fut1-deficient mice showed a significantly higher production of interleukin-4 (IL-4) and IL-6 in skin lesions compared with that of their WT counterparts. The expression of chemokines, particularly Ccl2 and Ccl8 , was notably higher in Fut1-deficient mice compared with those of WT mice. The infiltration of CD4 + T cells, eosinophils, and mast cells into the lesional skin was significantly elevated in Fut1-deficient mice compared with that in WT mice. These findings demonstrate the protective role of H2 antigen expression against AD-like inflammation and highlight its potential therapeutic impact on AD through the regulation of blood group antigens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Oh, Suh, Jin, Lee, Lee and Chung.)

Esophageal cancer (ESCA) is a high-incidence disease worldwide, of which the 5-year survival rate remains dismal since the cellular basis of ESCA remains largely unclear. Herein, we attempted to examine the manifestation of fucosyltransferase-6 (FUT6) in ESCA and the associated mechanisms. The GSE161533 dataset was used to analyze a crucial gene in ESCA. The expression of FUT6 was investigated in normal esophageal epithelial cells and ESCA cell lines. Following FUT6 knockdown or overexpression, cell proliferation, migration, invasion, and levels of epithelial–mesenchymal transition (EMT)-related and epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) signaling pathway-related proteins were evaluated using CCK-8, Transwell, and Western blotting with antibodies against EGFR, p-EGFR, E-cadherin, Vimentin, N-cadherin, ERK1/2, and p-ERK1/2), respectively. EGF was administered to stimulate the EGFR/ERK signaling pathway, followed by the assessment of cellular activity. Database analysis revealed that FUT6 was downregulated in the ESCA cells. Our study indicated that FUT6 is suppressed in various ESCA cell lines. Moreover, cell proliferation, invasion, migration, and EMT-related protein levels were conspicuously enhanced or restrained by FUT6 disruption or overexpression. FUT6 overexpression suppressed the malignant activities of the cells when stimulated by EGF, including inhibition of cell growth, movement, invasion, and EMT advancement, as well the reduction the levels of EGFR/ERK pathway proteins. In conclusion, FUT6 can suppress the EGFR/ERK signaling pathway activated by EGF, leading to the potential attenuation of ESCA cell proliferation, invasion, migration, and EMT.

2'-Fucosyllactose (2'-FL), one of the major human milk oligosaccharides, was produced in several engineered microorganisms. However, the low solubility of α-1,2-fucosyltransferase (α1,2-FucT) often becomes a bottleneck to produce maximum amount of 2'-FL in the microorganisms. To overcome this solubility issue, the following studies were conducted to improve the soluble expression of α1,2-FucT. Initially, hydrophobic amino acids in the hydrophilic region of the 6 α-helices were mutated, adhering to the α-helix rule. Subsequently, gfp11 was fused to the C-terminal of futC gene encoding α1,2-FucT (FutC), enabling selection of high-fluorescence mutants through split-GFP. Each mutant library was screened via fluorescence activated cell sorting (FACS) to separate soluble mutants for high-throughput screening. As a result, L80C single mutant and A121D/P124A/L125R triple mutant were found, and a combined quadruple mutant was created. Furthermore, we combined mutations of conserved sequences (Q150H/C151R/Q239S) of FutC, which showed positive effects in the previous studies from our lab, with the above quadruple mutants (L80C/A121D/P124A/L125R). The resulting strain produced approximately 3.4-fold higher 2'-FL titer than that of the wild-type, suggesting that the conserved sequence mutations are an independent subset of the mutations that further improve the solubility of the target protein acquired by random mutagenesis using split-GFP., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests or personal relationships that could have influenced the work reported in this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The aim of this study was to identify effective genetic markers for the Antigen Processing Associated Transporter 1 ( TAP1 ), α (1,2) Fucosyltransferase 1 ( FUT1 ), Natural Resistance Associated Macrophage Protein 1 ( NRAMP1 ), Mucin 4 ( MUC4 ) and Mucin 13 ( MUC13 ) diarrhea-resistance genes in the local pig breeds, namely Shanghai white pigs, Fengjing pigs, Shawutou pigs, Meishan pigs and Pudong white pigs, to provide a reference for the characterization of local pig breed resources in Shanghai. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLR) and sequence sequencing were applied to analyze the polymorphisms of the above genes and to explore the effects on the immunity of Shanghai local pig breeds in conjunction with some immunity factors. The results showed that both TAP1 and MUC4 genes had antidiarrheal genotype GG in the five pig breeds, AG and GG genotypes of the FUT1 gene were detected in Pudong white pigs, AA antidiarrheal genes of the NRAMP1 gene were detected in Meishan pigs, the AB type of the NRAMP1 gene was detected in Pudong white pigs, and antidiarrheal genotype GG of the MUC13 gene was only detected in Shanghai white pigs. The MUC13 antidiarrhea genotype GG was only detected in Shanghai white pigs. The TAP1 gene was moderately polymorphic in Shanghai white pigs, Fengjing pigs, Shawutou pigs, Meishan pigs and Pudong white pigs, among which TAP1 in Shanghai white pigs and Shawutou pigs did not satisfy the Hardy-Weinberg equilibrium. The FUT1 gene of Pudong white pigs was in a state of low polymorphism. NRAMP1 of Meishan pigs and Pudong white pigs was in a state of moderate polymorphism, which did not satisfy the Hardy-Weinberg equilibrium. The MUC4 genes of Shanghai white pigs and Pudong white pigs were in a state of low polymorphism, and the MUC4 genes of Fengjing pigs and Shawutou pigs were in a state of moderate polymorphism, and the MUC4 genes of Fengjing pigs and Pudong white pigs did not satisfy the Hardy-Weinberg equilibrium. The MUC13 gene of Shanghai white pigs and Pudong white pigs was in a state of moderate polymorphism. Meishan pigs had higher levels of IL-2, IL-10, IgG and TNF-α, and Pudong white pigs had higher levels of IL-12 than the other pigs. The level of interleukin 12 (IL-12) was significantly higher in the AA genotype of the MUC13 gene of Shanghai white pigs than in the AG genotype. The indicator of tumor necrosis factor alpha (TNF-α) in the AA genotype of the TAP1 gene of Fengjing pigs was significantly higher than that of the GG and AG genotypes. The indicator of IL-12 in the AG genotype of the Shawutou pig TAP1 gene was significantly higher than that of the GG genotype. The level of TNF-α in the AA genotype of the NRAMP1 gene of Meishan pigs was markedly higher than that of the AB genotype. The IL-2 level of the AG type of the FUT1 gene was obviously higher than that of the GG type of Pudong white pigs, the IL-2 level of the AA type of the MUC4 gene was dramatically higher than that of the AG type, and the IgG level of the GG type of the MUC13 gene was apparently higher than that of the AG type. The results of this study are of great significance in guiding the antidiarrhea breeding and molecular selection of Shanghai white pigs, Fengjing pigs, Shawutou pigs, Meishan pigs and Pudong white pigs and laying the foundation for future antidiarrhea breeding of various local pig breeds in Shanghai.

Fucosyltransferases (Fut) regulate the fucosylation process associated with tumorogenesis in different cancer types. Ascitic fluid (AF) from patients diagnosed with advanced stage of epithelial ovarian cancer (EOC) is considered as a dynamic tumor microenvironment associated with poor prognosis. Previous studies from our laboratory showed increased fucosylation in SKOV-3 and OVCAR-3, cancer-derived cell lines, when these cells were incubated with AFs derived from patients diagnosed with EOC. In the present work we studied three fucosyltransferases (Fut 2, Fut 4, and Fut 8) in SKOV-3, OVCAR-3 and CAOV-3 cell lines in combination with five different AFs from patients diagnosed with this disease, confirming that all tested AFs increased fucosylation. Then, we demonstrate that mRNAs of these three enzymes were overexpressed in the three cell lines under treatment with AFs. SKOV-3 showed the higher overexpression of Fut 2, Fut 4, and Fut 8 in comparison with the control condition. We further confirmed, in the SKOV-3 cell line, by endpoint PCR, WB, and confocal microscopy, that the three enzymes were overexpressed, being Fut 4 the most overexpressed enzyme compared to Fut 2 and Fut 8. These enzymes were concentrated in vesicular structures with a homogeneous distribution pattern throughout the cytoplasm. Moreover, we found that among the three enzymes, only Fut 4 was located inside the nuclei. The nuclear location of Fut 4 was confirmed for the three cell lines. These results allow to propose Fut 2, Fut 4, and Fut 8 as potential targets for EOC treatment or as diagnostic tools for this disease., (© 2024 International Federation for Cell Biology.)

Probiotics have gained significant attention as a potential strategy to improve health by modulating host-microbe interactions, particularly in situations where the normal microbiota has been disrupted. However, evidence regarding their efficacy has been inconsistent, with considerable interindividual variability in response. We aimed to explore whether a common genetic variant that affects the production of mucosal α(1,2)-fucosylated glycans, present in around 20% of the population, could explain the observed interpersonal differences in the persistence of commonly used probiotics. Using a mouse model with varying α(1,2)-fucosylated glycans secretion (Fut2WT or Fut2KO), we examined the abundance and persistence of Bifidobacterium strains (infantis, breve, and bifidum). We observed significant differences in baseline gut microbiota characteristics between Fut2WT and Fut2KO littermates, with Fut2WT mice exhibiting enrichment of species able to utilize α(1,2)-fucosylated glycans. Following antibiotic exposure, only Fut2WT animals showed persistent engraftment of Bifidobacterium infantis, a strain able to internalize α(1,2)-fucosylated glycans, whereas B. breve and B. bifidum, which cannot internalize α(1,2)-fucosylated glycans, did not exhibit this difference. In mice with an intact commensal microbiota, the relationship between secretor status and B. infantis persistence was reversed, with Fut2KO animals showing greater persistence compared to Fut2WT. Our findings suggest that the interplay between a common genetic variation and antibiotic exposure plays a crucial role in determining the dynamics of B. infantis in the recipient gut, which could potentially contribute to the observed variation in response to this commonly used probiotic species., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

Objective: Aim: To find any association between specific ABO blood groups and FUT2 secretory status and COVID-19 in a sample of Iraqi dentists., Patients and Methods: Materials and Methods: For each participant, a questionnaire including demography, COVID-19 status, blood grouping, and RH factor, with chemo-sensitive symptoms was recorded. The saliva samples were collected and DNA was extracted from leukocytes. Sequencing of molecular detection of the FUT2 gene by real-time PCR and the data was done, whilst drawing the phylogenetic tree., Results: Results: Out of 133, most of the dentists were female 61%, most were just under 35 years of age. The most participants in this study were predominantly with blood group O (40%), followed by B, A, and AB, with (90%) of them were RH+. All blood grouping and RH factor were high significantly associated with COVID-19 infection and its frequency (p<0.001). A significant association between smell dysfunction and infected blood group A and RH+ (p =0.044, 0.038) while taste dysfunction was negatively and significantly correlated with AB group (r=-0.73; p=0.008). The FUT2 secretor showed a significant association with COVID-19 infection and frequency. The majority of COVID-19-infected participants experienced a significant loss of both smell and taste with fast recovery within 2 weeks., Conclusion: Conclusions: The COVID-19 infection susceptibility and reinfection are associated with FUT2 secretory status and greatly associated to olfactory and gustatory sense loss.

To investigate the serological and genetic characteristics of para-Bombay patients in a hospital in Hunan Province. A retrospective analysis was conducted on the blood type results of 175 439 hospitalized patients born in Hunan Province from the Third Xiangya Hospital, Central South University from 2016 to 2021. Phenotypes of ABO blood group was analyzed by blood group serology, and molecular biological methods were used to analyze the genotype, including ABO genotyping by polymerase chain reaction-sequence specific primers (PCR-SSP) and fucosyltransferase 1 ( FUT1) and fucosyltransferase 2 ( FUT2) gene sequencing. The results showed that 3 cases of A h and 1 case of B h were detected. FUT1 sequencing showed that there were 2 cases of h3h3 , 1 case of h1h1 and 1 case of h 302 h1 , of which h 302 (c.302C>T) was the first discovered mutation. FUT2 sequencing revealed that 4 cases were all Se 357 Se 357 . The pedigree study showed that the inheritance of para-Bombay blood group was consistent with autosomal dominant inheritance. In conclusion, the FUT1 g ene mutations leading to para-Bombay blood group mainly include h3 , h1 and h 302 , of which h3 mutation is the most common.

Background and Objectives: The FUT2 gene is responsible for the synthesis of the H antigen in body secretions. It is highly polymorphic and population specific. We investigated the FUT2 gene polymorphism in Chinese blood donors and found a novel deletion mutation in one non-secretor individual. This study aimed to identify mutation(s) responsible for a non-secretor phenotype., Materials and Methods: The Lewis blood group of a Chinese Han blood donor was typed using the standard serological technique and the FUT2 gene of the sample was analysed by Sanger sequencing. Clone sequencing was performed for determining the haplotype of the FUT2 gene. Bioinformatics tools were used for predicting the effect of the deletion on the FUT2 gene., Results: A novel nine-base deletion (c.461&#95;469delGGACCTTCT) in the FUT2 gene was identified in a Chinese Han blood donor. Two haplotypes Se 390,418 and se 204,249,461&#95;469del,772,993 were determined by clone sequencing. According to the prediction of bioinformatics tools, the mutation at c.461&#95;469delGGACCTTCT might not influence the activity of the Se enzyme., Conclusion: We identified a new FUT2 mutation, the deletion of nine bases (c.461&#95;469delGGACCTTCT), in a Chinese Han blood donor. This deletion was reported for the first time., (© 2023 International Society of Blood Transfusion.)

Early-onset colorectal cancer (EOCRC) has been increasing worldwide. Potential risk factors may have occurred in childhood or adolescence. We investigated the associations between early-life factors and EOCRC risk, with a particular focus on long-term or recurrent antibiotic use (LRAU) and its interaction with genetic factors. Data on the UK Biobank participants recruited between 2006 and 2010 and followed up to February 2022 were used. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) of the associations between LRAU during early life and EOCRC risk overall and by polygenic risk score (constructed by 127 CRC-related genetic variants) and Fucosyltransferase 2 (FUT2), a gut microbiota regulatory gene. We also assessed the associations for early-onset colorectal adenomas, as precursor lesion of CRC, to examine the effect of LRAU during early-life and genetic factors on colorectal carcinogenesis. A total of 113 256 participants were included in the analysis, with 165 EOCRC cases and 719 EOCRA cases. LRAU was nominally associated with increased risk of early-onset CRC (OR = 1.48, 95% CI = 1.01-2.17, P = .046) and adenomas (OR = 1.40, 95% CI = 1.17-1.68, P < .001). When stratified by genetic polymorphisms of FUT2, LRAU appeared to confer a comparatively greater risk for early-onset adenomas among participants with rs281377 TT genotype (OR = 1.10, 95% CI = 0.79-1.52, P = .587, for CC genotype; OR = 1.75, 95% CI = 1.16-2.64, P = .008, for TT genotype; P interaction  = .089). Our study suggested that LRAU during early life is associated with increased risk of early-onset CRC and adenomas, and the association for adenomas is predominant among individuals with rs281377 TT/CT genotype. Further studies investigating how LRAU contributes together with genetic factors to modify EOCRC risk, particularly concerning the microbiome-related pathway underlying colorectal carcinogenesis, are warranted., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics 1 ., (© 2023. The Author(s).)

Background: In Western populations, pancreatic ductal adenocarcinoma (PDAC) risk has been found to be greater among individuals with non-O blood types than those with O blood type. However, the association has not been fully evaluated with respect to FUT2 (determining secretor status) and FUT3 (determining Lewis antigens) status, two biologically important genes in the expression of ABO blood groups with PDAC., Methods: We examined interactions in data from 8,027 cases and 11,362 controls in large pancreatic cancer consortia (PanScan I-III and PanC4) by using genetic variants to predict ABO blood groups (rs505922 and rs8176746), secretor status (rs601338), and Lewis antigens (rs812936, rs28362459, and rs3894326). Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) of the risk of PDAC adjusted for age and sex. We examined multiplicative interactions of ABO with secretor status and Lewis antigens by considering each product term between ABO and secretor and between ABO and Lewis antigens individually., Results: We found that the increased risk associated with non-O blood groups was somewhat stronger among secretors than nonsecretors [ORs, 1.28 (95% CI, 1.15-1.42) and 1.17 (95% CI, 1.03-1.32) respectively; Pinteraction = 0.002]. We did not find any interactions between ABO and Lewis antigens., Conclusions: Our large consortia data provide evidence of effect modification in the association between non-O blood type and pancreatic cancer risk by secretor status., Impact: Our results indicate that the association between ABO blood type and PDAC risk may vary by secretor status, but not by Lewis antigens., (©2023 American Association for Cancer Research.)

Backgrounds: Renal fibrosis is a common pathologic process of most chronic kidney diseases (CKDs), becoming one of the major public health problems worldwide. Terminal fucosylation plays an important role in physiological homeostasis and pathological development. The present study aimed to explore the role of terminal fucosylation during kidney fibrogenesis and propose a possible anti-fibrosis treatment via suppressing aberrant terminal fucosylation., Methods: We investigated the expression level of fucosyltransferase1 (FUT1) in CKD patients by using public database. Then, we further confirmed the level of terminal fucosylation by UEA-I staining and FUT1 expression in unilateral ureteral obstruction (UUO)-induced renal fibrosis mice. Immunostaining, qPCR, western blotting and wound healing assay were applied to reveal the effect of FUT1 overexpression in human kidney proximal tubular epithelial cell (HK-2). What's more, we applied terminal fucosylation inhibitor, 2-Deoxy-D-galactose (2-D-gal), to determine whether suppressing terminal fucosylation ameliorates renal fibrosis progression in vitro and in vivo., Results: Here, we found that the expression of FUT1 significantly increased during renal fibrosis. In vitro experiments showed upregulation of epithelial-mesenchymal transition (EMT) after over-expression of FUT1 in HK-2. Furthermore, in vivo and in vitro experiments indicated that suppression of terminal fucosylation, especially on TGF-βR I and II, could alleviate fibrogenesis via inhibiting transforming growth factor-β (TGF-β)/Smad signaling., Conclusions: The development of kidney fibrosis is attributed to FUT1-mediated terminal fucosylation, shedding light on the inhibition of terminal fucosylation as a potential therapeutic treatment against renal fibrosis., (© 2023. The Author(s).)

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 ΔISC (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., Competing Interests: Declarations of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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 △IEC 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 △IEC 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., (© 2023. The Author(s).)

The incidence of colorectal cancer (CRC), a leading cause of cancer‑related mortality, has increased globally. Fucosyltransferase 2 (FUT2), catalyzing the α1, 2‑linked fucose in mammals, has been reported to be overexpressed in several malignant cancers, including CRC. However, the effects of FUT2 on CRC remain largely unknown. Herein, it was determined that the FUT2 expression levels in CRC tissues were higher than those in adjacent non‑tumor tissues, whereas no association with tumor stage was revealed. The results of biological functional analysis revealed that FUT2 knockdown inhibited the proliferation, migration and invasion of human CRC cells. Moreover, the knockdown of FUT2 arrested the CRC cells at the G0/G1 phase and promoted the apoptosis of human CRC cells. Western blot analysis demonstrated that the expression levels of β‑catenin, C‑myc and cyclin D1 were decreased by FUT2 knockdown in CRC cells, whereas the expression of glycogen synthase kinase‑3β and the phosphorylation levels of β‑catenin were increased. Additionally, Wnt2 was fucosylated by FUT2 in CRC cells. Furthermore, the knockdown of FUT2 inhibited the growth of human CRC in vivo . Overall, the findings of the present study suggest that FUT2 may be used as a potential diagnostic biomarker and therapeutic target for CRC treatment.

In mammals fucosyltransferase 2 (FUT2) plays an important regulatory role in inflammation, bacterial or viral infection, and tumor metastasis. However, the specific role of FUT2 in invertebrate immunity has not been reported. Here, the FUT2 homolog of Penaeus vannamei (designated as PvFUT2) was cloned and found to have a full-length cDNA of 1104 bp with an open reading frame (ORF) encoding 316 amino acids. PvFUT2 is constitutively expressed in all shrimp tissues tested with the highest found in intestines. Moreover, PvFUT2 was induced in the main immune organs (hemocytes and hepatopancreas) of shrimp by Gram-positive (Vibrio parahaemolyticus), Gram-negative (Streptococcus iniae) bacteria and virus (White Spot Syndrome Virus), indicating the involvement of PvFUT2 in shrimp antimicrobial response. Intriguingly, PvFUT2 knockdown with or without pathogen challenge reduced the expression of Pvβ-catenin and antimicrobial peptides genes, particularly anti lipopolysaccharide factor and lysozyme. Further analysis revealed that the knockdown of PvFUT2 increased Vibrio abundance in hemolymph and resulted in an increase in shrimp cumulative mortality rate. Thus, during pathogen challenge, the expression of PvFUT2 is induced to regulate β-catenin and subsequently antimicrobial peptides expression to augment shrimp antimicrobial immune response., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Our previous study showed that fucosyltransferase 2 (Fut2) deficiency is closely related to colitis. Colitis increases the risk for the development of colorectal cancer (CRC). This study aimed to investigate the effect and underlying mechanism of action of Fut2 in CRC., Methods: Intestinal epithelium-specific Fut2 knockout (Fut2 △IEC ) mice were used in this study. CRC was induced using azoxymethane (AOM) and dextran sulfate sodium (DSS). Immunofluorescence was used to examine the fucosylation levels. Proteomics and N-glycoproteomics analyses, Ulex Europaeus Agglutinin I (UEA-I) affinity chromatography, immunoprecipitation, and rescue assay were used to investigate the mechanism of Fut2 in CRC., Results: The expression of Fut2 and α-1,2-fucosylation was lower in colorectal tumor tissues than in the adjacent normal tissues of AOM/DSS-induced CRC mice. More colorectal tumors were detected in Fut2 △IEC mice than in control mice, and significant downregulation of melanoma cell adhesion molecule (MCAM) fucosylation was detected in the colorectal tumor tissues of Fut2 △IEC mice. Overexpression of Fut2 inhibited cell proliferation, invasion and tumor metastasis in vivo and in vitro in SW480 and HCT116 cells. Moreover, fucosylation of MCAM may be a mediator of Fut2 in CRC. Peracetylated 2-F-Fuc, a fucosyltransferase inhibitor, repressed fucosylation modification of MCAM and reversed the inhibitory effects of Fut2 overexpression on SW480 cell proliferation, migration, and invasion. Our results indicate that Fut2 deficiency in the intestinal epithelium promotes CRC by downregulating the fucosylation of MCAM., Conclusions: The regulation of fucosylation may be an potential therapy for CRC, especially in patients with Fut2 gene defects., (© 2023. The Author(s).)

A major polymorphism in the fucosyltransferase2 (FUT2) gene influences risk of multiple gut diseases, but its impact on the microbiome of breastfed infants was unknown. In individuals with an active FUT2 enzyme (“secretors”), the intestinal mucosa is abundantly fucosylated, providing mutualist bacteria with a rich endogenous source of fucose. Non-secretors comprise approximately one-fifth of the population, and they lack the ability to create this enzyme. Similarly, maternal secretor status influences the abundance of a breastfeeding mother’s fucosylated milk oligosaccharides. We compared the impact of maternal secretor status, measured by FUT2 genotype, and infant secretor status, measured by FUT2 genotype and phenotype, on early infant fecal microbiome samples collected from 2-month-old exclusively breastfed infants (n = 59). Infant secretor status (19% non-secretor, 25% low-secretor, and 56% full-secretor) was more strongly associated with the infant microbiome than it was with the maternal FUT2 genotype. Alpha diversity was greater in the full-secretors than in the low- or non-secretor infants (p = 0.049). Three distinct microbial enterotypes corresponded to infant secretor phenotype (p = 0.022) and to the dominance of Bifidobacterium breve, B. longum, or neither (p < 0.001). Infant secretor status was also associated with microbial metabolic capacity, specifically, bioenergetics pathways. We concluded that in exclusively breastfed infants, infant—but not maternal—secretor status is associated with infant microbial colonization and metabolic capacity.

Phaeodactylum tricornutum (Pt) is a critical microbial cell factory to produce a wide spectrum of marketable products including recombinant biopharmaceutical N-glycoproteins. N-glycosylation modification of proteins is important for their activity, stability, and half-life, especially some special modifications, such as fucose-modification by fucosyltransferase (FucT). Three PtFucTs were annotated in the genome of P. tricornutum, PtFucT1 was located on the medial/trans-Golgi apparatus and PtFucT2-3 in the plastid stroma. Algal growth, biomass and photosynthesis efficiency were significantly inhibited in a knockout mutant of PtFucT1 (PtFucT1-KO). PtFucT1 played a role in non-core fucose modification of N-glycans. The knockout of PtFucT1 might affect the activity of PtGnTI in the complex and change the complex N-glycan to mannose type N-glycan. The study provided critical information for understanding the mechanism of protein N-glycosylation modification and using microalgae as an alternative ecofriendly cell factory to produce biopharmaceuticals., (© 2023. The Author(s).)

Background: The goal was to identify a novel FUT1 allele and to study serologic and gene feature of the para-Bombay blood type of one expectant mother in Xinjiang, China., Methods: ABO and Lewis groups were recognized by standard serologic techniques in an ABO typing discrepancy specimen from one person at the Tianjin Blood Center. DNA (deoxyribonucleic acid) was collected and polymerase chain reactions with sequence-specific primers (PCR-SSP) were performed to sequence exons 6 and 7 of ABO gene, exon 4 of FUT1 gene, and exon 2 of FUT2. PCR products were sequenced to identify ABO groups and the variation sites. The genotype was determined by family study., Results: In our laboratory testing, erythrocytes from the proposita did not react with anti-A and anti-B reagents. B antigen was discovered only after adsorption and elution. Red cells were nonreactive with monoclonal anti-H. The sera of the proposita contained anti-A and were weakly agglutinated by B cells. The hybrid 902 A>G mutation was detected in the proposita's father and mother. The proposita has the same mutation 902 A>G, which was conjectured as homozygosity for 902 A>G., Conclusions: One novel mutation of FUT1 gene was observed in our laboratory. It has never been reported previously. The para-Bombay phenotype in the proposita originating from Xinjiang (China) results from homozygosity for FUT1 902 A>G, together with 357 C>T of FUT2.

Background: Many indigenous peoples are at elevated risk for otitis media, however there is limited information on hearing loss due to OM in these communities. An Indigenous Filipino community that has previously been described with an elevated prevalence of OM that is due to rare A2ML1 variants and a common FUT2 variant underwent additional phenological testing. In this study, we describe the audiologic profiles in A2ML1 - and FUT2 -related otitis media and the validity of otoscopy and genotyping for A2ML1 and FUT2 variants in screening for otitis media and hearing loss. Method: We analyzed A2ML1 and FUT2 genotypes together with demographic, otologic and audiologic data from tympanometry and hearing level assessments of 109 indigenous individuals. Results: We confirmed previous findings of a spectrum of nonsyndromic otitis media as associated with A2ML1 variants. A2ML1 and FUT2 variants were associated with high-frequency hearing loss at 4000 Hz. As expected, young age was associated with flat tympanograms, and eardrum perforations due to chronic otitis media were associated with severe-to-profound hearing loss across frequencies. Adding A2ML1 or FUT2 genotypes improved the validity of otoscopy as a screening test to rule out moderate-to-profound hearing loss. Conclusion: Continued multi-disciplinary management and audiologic follow-up using tympanometry and screening audiometry are needed to document and treat otitis media and prevent permanent hearing loss in the indigenous community.

Lung cancer is the most common cancer with high morbidity and mortality worldwide. Our previous studies showed that fucosyltransferase 2 (FUT2) is highly expressed in lung adenocarcinoma (LUAD) and plays a vital role in the tumorigenesis of LUAD. However, the underlying mechanism is not fully understood. Autophagy has recently attracted increasing attention due to its pro-survival role in cancer progression and metastasis. Here, we found that FUT2 was up-regulated and had an AUC (Area Under Curve) value of 0.964 in lung adenocarcinoma based on the TCGA dataset. Knockdown of FUT2 weakened the autophagy response, as evidenced by a degradation of LC3-II and Beclin1. The phosphorylation levels of AMPK, ULK1, and PI3K III were significantly reduced by FUT2 knockdown. FUT2 promoted the translocation of p53 from the cytoplasm into the nucleus, which triggered the DRAM1 pathway and enhanced autophagy. Meanwhile, the knockdown of FUT2 increased the phosphorylation of JNK and promoted mitochondrial-mediated apoptosis. Furthermore, the knockdown of FUT2 inhibited the autophagy induced by Z-VAD-FMK and promoted the apoptosis suppressed by rapamycin. The autophagy and apoptosis regulated by FUT2 antagonized each other. Taken together, these findings provide a mechanistic understanding of how FUT2 mediated the crosstalk between autophagy and apoptosis, which determine lung cancer cell death and survival, leading to the progression of lung adenocarcinoma.

Protein O-fucosyltransferase 2 (PoFUT2) is an inverting glycosyltransferase (GT) that fucosylates thrombospondin repeats (TSRs) from group 1 and 2. PoFUT2 recognizes a large and diverse number of TSRs through a dynamic network of water-mediated interactions. By X-ray structural studies of C. elegans PoFUT2 complexed to a TSR of group 2, we demonstrate that this GT recognizes similarly the 3D structure of TSRs from both groups 1 and 2. Its active site is highly exposed to the solvent, suggesting that water molecules might also play an essential role in the fucosylation mechanism. We applied QM/MM methods using human PoFUT2 as a model, and found that HsPoFUT2 follows a classical S N 2 reaction mechanism in which water molecules contribute to a great extent in facilitating the release of the leaving pyrophosphate unit, causing the H transfer from the acceptor nucleophile (Thr/Ser) to the catalytic base, which is the last event in the reaction. This demonstrates the importance of water molecules not only in recognition of the ligands but also in catalysis., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Objective: To explore the genetic mechanism underlying a case with para-Bombay phenotype., Methods: The ABO and Lewis phenotype were identified with serological methods. The coding regions of exons 6 and 7 of the ABO and FUT1 genes were amplified with PCR and directly sequenced. Haploid sequence analysis was carried out on the variant sites of the FUT1 gene., Results: Serological analysis confirmed that the proband has a rare para-Bombay phenotype. Direct sequencing revealed that he was a B.01/O.01.02 heterozygote for the ABO gene, and had heterozygous deletion for the 768 and 881-882 sites of the FUT1 gene. Further haploid analysis showed that the c.881&#95;882delTT deletion has occurred in one haploid while c.768delC was present in the other haploid. The proband was therefore determined as a FUT1*01N.13/01N.20 heterozygote, which have resulted in frameshift in polypeptide chain p.Phe294Cysfs*40 and p.Val257Phefs*23, respectively., Conclusion: A rare bi-allelic heterozygous deletion of para-Bombay phenotype has been identified in a blood donor. The c.881&#95;882delTT and c.768delC deletions may decrease the activity of α-1,2-fucosyltransferase.

Fucosyltransferase 2 (FUT2) and 3 (FUT3) may influence host biological functions. We aim to assess the relationship between maternal and child FUT2 (Secretor) and FUT3 (Lewis) status with growth, body composition, gut health and histologic features in Bangladeshi children. We conducted a case-control study where secretor and Lewis status were ascertained from saliva samples of 408 mother-child dyads. Upper-arm fat area estimate (UFE) and total upper arm area (TUA) were found higher among children of Lewis negative mothers (p = 0.01 and p = 0.07, respectively). Changes in UFE after nutrition intervention were significantly greater among Lewis positive children than those of negative for Lewis (p = 0.05). Significant differences were observed for child UFE based on secretor and Lewis status of the mothers (p = 0.04). Lewis positive children had greater changes in WAZ (p = 0.07) and WLZ (p = 0.02) than Lewis negative children at the end of nutrition intervention. Fecal Reg1B was elevated in secretor positive children compared to their counterparts (p = 0.03). Lewis negative children had higher concentrations of MPO compared to Lewis positive children (p = 0.08). We also observed a higher frequency of subtotal villous atrophy among secretor negative and Lewis positive children (p = 0.09 and p = 0.01, respectively) than those of their counterparts. The findings provide insights for further studies to elucidate causal influences., (© 2022. The Author(s).)

Objective: Some obese subjects with genetic variants of FUT2 gene could be implied in metabolic disorders. The aim of the present investigation was to evaluate the association between SNP rs602662 in FUT2 gene with different obesity markers., Subjects and Methods: 166 Caucasian obese subjects were enrolled. Anthropometric parameters, blood pressure, fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), lipid profile, C reactive protein and prevalence of metabolic syndrome were recorded. The genotype of FUT2 gene polymorphism (rs602662) was evaluated., Results: The genotype distribution of the rs602662 variant was the following: 29.5% (n=49) (GG), 47.6% (n=79) (GA) and 22.9% (n=38) (AA). We observed statistical differences between both genotypes (GG+GA vs. AA) in BMI (Delta: 0.4±0.01 kg/m2: p=0.04), fat mass (Delta: 3.7±0.3 kg: p=0.02), body weight (Delta: 5.9±0.4 kg: p=0.02), waist circumference (Delta: 7.3+0.9 cm: p=0.03), glucose (Delta: 5.5±0.4 mg/dl: p=0.04), triglycerides (Delta: 25.9±1.4 mg/dl: p=0.01), HDL-cholesterol (Delta: -5.7±1.2 mg/dl: p=0.02), insulin (Delta: 5.0±0.9 mUI/L: p=0.02) and HOMA-IR (Delta: 1.4±0.1 units: p=0.03) levels. Percentages of metabolic syndrome, central obesity, hypertriglyceridemia, low HDL cholesterol and hyperglycemia were lower in AA obese subjects than GG+GA. Logistic regression analysis showed a decreased risk of metabolic syndrome in AA subjects (OR=0.28, 95% CI=0.11-0.71, p=0.01)., Conclusions: AA genotype of FUT2 rs602662 is associated with lower BMI and a better metabolic profile than subjects with GG+GA genotypes.

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.

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care 1 or hospitalization 2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease., (© 2022. The Author(s).)

Background: Fucosyltransferase 2 (FUT2) participates in intestinal antigen secretion and bacterial adherence. FUT2 homozygous nonsense mutations (FUT2M) and subsequent nonsecretor status is associated with Crohn's disease (CD). The common null allele is rs601338. We assessed the relationship between FUT2M and disease course., Methods: In consecutive adult CD outpatients, clinical, biochemical, and genetic data were collected at baseline visits. Patients were longitudinally followed over 5 years. The primary outcome analyzed the relationship between FUT2M and rates of CD patients in persistent steroid-free clinical remission requiring neither surgery, biologics, nor immunomodulators., Results: Sixty-two CD patients were recruited. FUT2M homozygotes (rs601338 or any mutation in linkage disequilibrium) were detected in 27% of CD (17/62). Patients with rs601338 mutations had higher rates of the primary outcome (homozygous: 46.6%, heterozygous: 28.0%, wild-type: 5.3%, P=0.02). Similar findings existed for CD patients with homozygous mutations in any single-nucleotide polymorphism for FUT2 (homozygous: 41.2%, heterozygous: 25.9%, wild-type: 5.6%, P=0.04). On multivariable analysis, rs601338 mutation was associated with the primary outcome (odds ratio=3.4, 95% confidence interval: 1.3-8.7, P=0.01), while other parameters were not. Mutation of rs601338 was associated with lower rates of penetrating disease (homozygous: 13.3%, heterozygous: 28.0%, wild-type: 52.6%, P=0.05) and particularly in high-risk patients (homozygous: 0%, heterozygous: 37.5%, wild-type: 83.3%, P=0.01)., Conclusions: FUT2 mutation status is associated with a favorable clinical course in CD. Further confirmatory studies are needed., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The human gut microbiome is a complex ecosystem that is involved in its host's metabolism, immunity and health. Although interindividual variations in gut microbial composition are mainly driven by environmental factors, some gut microorganisms are heritable and thus can be influenced by host genetics. In the past 5 years, 12 microbial genome-wide association studies (mbGWAS) with >1,000 participants have been published, yet only a few genetic loci have been consistently confirmed across multiple studies. Here we discuss the state of the art for mbGWAS, focusing on current challenges such as the heterogeneity of microbiome measurements and power issues, and we elaborate on potential future directions for genetic analysis of the microbiome., (© 2022. Springer Nature America, Inc.)

Host genetics are known to influence the gut microbiome, yet their role remains poorly understood. To robustly characterize these effects, we performed a genome-wide association study of 207 taxa and 205 pathways representing microbial composition and function in 7,738 participants of the Dutch Microbiome Project. Two robust, study-wide significant (P < 1.89 × 10 -10 ) signals near the LCT and ABO genes were found to be associated with multiple microbial taxa and pathways and were replicated in two independent cohorts. The LCT locus associations seemed modulated by lactose intake, whereas those at ABO could be explained by participant secretor status determined by their FUT2 genotype. Twenty-two other loci showed suggestive evidence (P < 5 × 10 -8 ) of association with microbial taxa and pathways. At a more lenient threshold, the number of loci we identified strongly correlated with trait heritability, suggesting that much larger sample sizes are needed to elucidate the remaining effects of host genetics on the gut microbiome., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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 Fut2 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., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Otitis media (OM) is a leading cause of childhood hearing loss. Variants in FUT2 , which encodes alpha-(1,2)-fucosyltransferase, were identified to increase susceptibility to OM, potentially through shifts in the middle ear (ME) or nasopharyngeal (NP) microbiotas as mediated by transcriptional changes. Greater knowledge of differences in relative abundance of otopathogens in carriers of pathogenic variants can help determine risk for OM in patients. In order to determine the downstream effects of FUT2 variation, we examined gene expression in relation to carriage of a common pathogenic FUT2 c.461G>A (p.Trp154*) variant using RNA-sequence data from saliva samples from 28 patients with OM. Differential gene expression was also examined in bulk mRNA and single-cell RNA-sequence data from wildtype mouse ME mucosa after inoculation with non-typeable Haemophilus influenzae (NTHi). In addition, microbiotas were profiled from ME and NP samples of 65 OM patients using 16S rRNA gene sequencing. In human carriers of the FUT2 variant, FN1, KMT2D, MUC16 and NBPF20 were downregulated while MTAP was upregulated. Post-infectious expression in the mouse ME recapitulated these transcriptional differences, with the exception of Fn1 upregulation after NTHi-inoculation. In the NP, Candidate Division TM7 was associated with wildtype genotype (FDR-adj- p =0.009). Overall, the FUT2 c.461G>A variant was associated with transcriptional changes in processes related to response to infection and with increased load of potential otopathogens in the ME and decreased commensals in the NP. These findings provide increased understanding of how FUT2 variants influence gene transcription and the mucosal microbiota, and thus contribute to the pathology of OM., Competing Interests: AR is a cofounder of Otonomy, Inc., serves as a consultant and member of the Scientific Advisory Board, and holds an equity position in the company. The UCSD and San Diego VA Committees on Conflict of Interest have approved this relationship. Otonomy, Inc. had no role in the conduct of this study and the writing of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elling, Scholes, Streubel, Larson, Wine, Bootpetch, Yoon, Kofonow, Gubbels, Cass, Robertson, Jenkins, Prager, Frank, Chan, Friedman, Ryan and Santos-Cortez.)

Acute respiratory infections (ARIs) are one of the most common causes of morbidity and mortality in young children. The aim of our study was to examine whether variation in maternal FUT2 (α1,2-fucosyltransferase 2) and FUT3 (α1,3/4-fucosyltransferase 3) genes, which shape fucosylated human milk oligosaccharides (HMOs) in breast milk, are associated with the occurrence of ARIs in breastfed infants as well as the influence of the nasopharyngeal microbiome on ARI risk. Occurrences of ARIs were prospectively recorded in a cohort of 240 breastfed Bangladeshi infants from birth to 2 years. Secretor and Lewis status was established by sequencing of FUT2/3 genes. The nasopharyngeal microbiome was characterized by shotgun metagenomics, complemented by specific detection of respiratory pathogens; 88.6% of mothers and 91% of infants were identified as secretors. Maternal secretor status was associated with reduced ARI incidence among these infants in the period from birth to 6 months (incidence rate ratio [IRR], 0.66; 95% confidence interval [CI], 0.47 to 0.94; P =  0.020), but not at later time periods. The nasopharyngeal microbiome, despite precise characterization to the species level, was not predictive of subsequent ARIs. The observed risk reduction of ARIs among infants of secretor mothers during the predominant breastfeeding period is consistent with the hypothesis that fucosylated oligosaccharides in human milk contribute to protection against respiratory infections. However, we found no evidence that modulation of the nasopharyngeal microbiome influenced ARI risk. IMPORTANCE The observed risk reduction of acute respiratory infections (ARIs) among infants of secretor mothers during the predominant breastfeeding period is consistent with the hypothesis that fucosylated oligosaccharides in human milk contribute to protection against respiratory infections. Respiratory pathogens were only weak modulators of risk, and the nasopharyngeal microbiome did not influence ARI risk, suggesting that the associated protective effects of human milk oligosaccharides (HMOs) are not conveyed via changes in the nasopharyngeal microbiome. Our observations add to the evidence for a role of fucosylated HMOs in protection against respiratory infections in exclusively or predominantly breastfed infants in low-resource settings. There is no indication that the nasopharyngeal microbiome substantially modulates the risk of subsequent mild ARIs. Larger studies are needed to provide mechanistic insights on links between secretor status, HMOs, and risk of respiratory infections.