Core fucosylation and its roles in gastrointestinal glycoimmunology

Glycosylation is a common post-translational modification in eukaryotic cells.It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function.Core fucosylation plays a vital role in the immune response.Most immune system molecules are core fucosylated glycoproteins such as complements,cluster differentiation antigens,immunoglobulins,cytokines,major histocompatibility complex molecules,adhesion molecules,and immune molecule synthesis-related transcription factors.These core fucosylated glycoproteins play important roles in antigen recognition and clearance,cell adhesion,lymphocyte activation,apoptosis,signal transduction,and endocytosis.Core fucosylation is dominated by fucosyltransferase 8(Fut8),which catalyzes the addition ofα-1,6-fucose to the innermost GlcNAc residue of N-glycans.Fut8 is involved in humoral,cellular,and mucosal immunity.Tumor immunology is associated with aberrant core fucosylation.Here,we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.

Association of fucosyltransferase 2 gene variants with ulcerative colitis in Han and Uyghur patients in China

AIM:To investigate the contribution of fucosyltransferase 2 (FUT2) variants to the genetic susceptibility and clinical heterogeneity of ulcerative colitis (UC) between Han and Uyghur patients in Xinjiang, China. METHODS:A total of 102 UC patients (53 Han patients including 22 men and 31 women, and 49 Uyghur patients including 25 men and 24 women; aged 48 ± 16 years) and 310 age-and sex-matched healthy controls were enrolled from January 2010 to May 2011 in Xinjiang People's Hospital of China. UC was diagnosed based on the clinical, endoscopic and histological findings following Lennard-Jones criteria. Blood samples were collected and genomic DNA was extracted by the routine laboratory methods. Polymerase chain reaction-sequence-based typing method was used to identify FUT2 variants rs281377, rs1047781, rs601338 and rs602662. Genotypic and allelic frequencies were documented and compared between the UC patients and the healthy controls. Genotypic frequencies were also compared between Han and Uyghur patients. Potential association of genetic variation and UC between Han and Uyghur patients was examined. RESULTS: rs281377 was found significantly associated with UC in the Han population as compared with the controls (P = 0.011) while rs281377 was not associated with UC in the Uyghur population (P = 0.06). TT homozygous rs281377 frequencies were higher in the UC groups than in the controls (88.7% vs 68.7% and 55.1% vs 50.3%). rs1047781 was specifically associated with UC in the Uyghur population (P = 0.001), but not associated with UC in the Han population (P = 0.13). TT homozygous rs1047781 frequencies were lower in the UC groups than in the controls (9.5% vs 11.8% and 4.0% vs 6.7%). rs601338 was statistically related to UC in both populations (Han, P = 0.025; Uyghur, P = 8.33 × 10 -5 ). AA homozygous rs601338 frequencies were lower in the UC groups than in the controls (0% vs 1.8% and 12.2% vs 13.4%). No association was found between rs602662 and UC in both Han and the Uyghur populations. Allelic analysis showed that rs281377 allele was significantly associated with UC in the Han population as compared with the controls [P = 0.001, odd ratio (OR) = 0.26], however, it was not associated with UC in the Uyghur population (P = 0.603, OR = 1.14), and rs1047781 allele was associated with UC in the Uyghur population (P = 0.001, OR = 0.029) while it was not associated with UC in the Han population (P = 0.074, OR = 0.62). Moreover, rs601338 was associated with UC in both Han (P = 0.005, OR = 0.1) and Uyghur pop- ulations (P = 0.002, OR = 0.43). Meta analysis showed that rs1047781 and rs601338 conferred risk of UC as compared with the controls [P = 0.005, OR = 0.47; P = 0.0003, OR = 0.35; 95% confidence interval (CI) = 0.31-0.72 and 0.21-0.58], but rs281377 and rs602662 showed no statistically significant differences betweenpatients with UC and controls (P = 0.10, OR = 0.71; P = 0.68, OR = 0.09; 95% CI = 0.47-1.07 and 0.56-1.47). CONCLUSION:Functionally relevant FUT2 gene variants are associated with UC, suggesting that they play a potential role in the pathogenesis of UC and may contribute to the clinical heterogeneity of UC between Han and Uyghur patients.

Correlation of FUT3 gene polymorphism with immune response and inflammatory response in patients with ulcerative colitis

Objective: To study the correlation of FUT3 gene polymorphism with immune response and inflammatory response in patients with ulcerative colitis (UC). Methods: Patients with UC and patients with irritable bowel syndrome who accepted endoscopic biopsy in the First Affiliated Hospital of Jiamusi University between May 2014 and April 2017 were selected as UC group and control group respectively, and the FUT3 gene polymorphism, immune transcription factor and inflammation molecule expression as well as immune cell contents in intestinal mucosa were determined. Results: FUT3 gene rs28362459 and rs3894326 locus genotype constituent ratio in intestinal mucosal tissue of UC group were not significantly different from those of control group whereas rs3745635 locus GA+AA genotype constituent ratio was significantly higher than that of control group;CD4+CD29+ and CD4+IL17A+ cell contents as well as HSF-2, NF-kB, Bax, TNF-α and IL-1β mRNA expression in mucosal tissue of UC group were significantly higher than those of control group whereas CD4+CD25+Foxp3+ cell content as well as SOCS2 and SOCS3 mRNA expression was significantly lower than those of control group;CD4+CD29+ and CD4+IL17A+ cell contents as well as HSF-2, NF-kB, Bax, TNF-α and IL-1β mRNA expression in UC group of mucosal tissue with FUT2 rs3745635 locus GA+AA genotype were significantly higher than those of UC group of mucosal tissue with GG genotype whereas CD4+CD25+Foxp3+ cell content as well as SOCS2 and SOCS3 mRNA expression was significantly lower than those in UC group of mucosal tissue with GG genotype. Conclusion: The FUT3 gene rs3745635 locus polymorphism in intestinal mucosa of UC is closely related to immune response and inflammatory response disorders.

Blocking Posttranslational Core Fucosylation Ameliorates Rat Peritoneal Mesothelial Cell Epithelial-Mesenchymal Transition

Background：Core fucosylation （CF）,catalyzed by α-1,6 fucosyltransferase （Fut8） in mammals,plays an important role in pathological processes through posttranslational modification of key signaling receptor proteins,including transforming growth factor （TGF）-β receptors and platelet-derived growth factor （PDGF） receptors.However,its effect on peritoneal fibrosis is unknown.Here,we investigated its influence on epithelial-mesenchymal transition （EMT） of rat peritoneal mesothelial cells （PMCs） in vitro induced by a high-glucose （HG） culture solution.Methods：Rat PMCs were first cultured in a HG （2.5%） culture solution to observe the CF expression level （fluorescein isothiocyanate-lens culinaris agglutinin）,we next established a knockdown model of rat PMCs in vitro with Fut8 small interfering RNA （siRNA） to observe whether inhibiting CF decreases the messenger RNA （mRNA） expression and protein expression of Fut8 and reverses EMT status.Rat PMCs were randomly divided into control group,mock group （transfected with scrambled siRNA）,Fut8 siRNA group,HG group,HG ＋ mock group,and HG ＋ Fut8 siRNA group.Finally,we examined the activation of TGF-β/Smad2/3 signaling and PDGF/extracellular signal-regulated kinase （ERK） signaling to observe the influence of CF on them.Results：CF,Fut8 mRNA,and protein expression were all significantly upregulated in HG-induced EMT model than those in the control rat PMCs （P 〈 0.05）.Fut8 siRNA successfully blocked CF of TGF-β receptors and PDGF receptors and attenuated the EMT status （E-cadherin and α-SMA and phenotypic changes） in HG-induced rat PMCs.In TGF-β/Smad2/3 signaling,Fut8 siRNA did not suppress the protein expression of TGF-3 receptors and Smad2/3;however,it significantly suppressed the phosphowlation of Smad2/3 （relative expression folds of HG ＋ Fut8 group vs.HG group：7.6 ± 0.4 vs.15.1 ± 0.6,respectively,P 〈 0.05）.In PDGF/ERK signaling,Fut8 siRNA did not suppress the protein expression of PDGF receptors and ERK,but it significantly suppressed the phosphorylation of ERK （relative expression folds of HG ＋ Fut8 group vs.HG group：8.7 ± 0.9 vs.15.6 ± 1.2,respectively,P 〈 0.05）.Blocking CF inactivated the activities of TGF-β and PDGF signaling pathways,and subsequently blocked EMT.Conclusions：These results demonstrate that CF contributes to rat PMC EMT.and that blocking it attenuates EMT.CF regulation is a potential therapeutic target of peritoneal fibrosis.