Inflammation-dependent changes in α2,3-, α2,6-, and α2,8-sialic acid glycotopes on serum glycoproteins in mice
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The expression of acute-phase serum proteins increases in response to inflammatory stimuli. Most of these proteins are glycoproteins that often contain sialic acids (Sia). It is unknown, however, how the expression of Sia in these glycoproteins changes during inflammation. This study demonstrates changes in the alpha2,3-, alpha2,6-, and alpha2,8-Sia glycotopes on serum glycoproteins in response to turpentine oil-induced inflammation, based on lectin- and immunoblot analyses by using sialyl linkage-specific lectins, Maackia amurensis for the alpha2,3-Sia glycotope and Sambucus sieboldiana for the alpha2,6-Sia glycotopes, and monoclonal antibody 2-4B (mAb.2-4B) recognizing the di- and oligomers of the alpha2,8-Neu5Gc residue. There was an increase in a limited number of sialoglycoproteins containing the alpha2,3-, alpha2,6-, or alpha2,8-Sia glycotopes. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression profiles of mRNAs for the known sialyltransferases in mouse liver during inflammation indicated the up-regulated expression of beta-galactoside alpha2,3-sialyltransferases (ST3Gal I and ST3Gal III) and beta-N-acetylgalactosaminide alpha2,6-sialyltransferase (ST6GalNAc VI) as well as beta-galactoside alpha2,6-sialyltransferase (ST6Gal I) mRNAs. Notably, ST3Gal I and III and ST6GalNAc VI are involved in the synthesis of the alpha2,3- and alpha2,6-Sia glycotopes on O-glycan chains and possibly on gangliosides, whereas ST6Gal I is specific for N-glycan chains. These results provide evidence for the inflammation-induced expression of sialyl glycotopes in serum glycoproteins. We demonstrated that inflammation significantly increased the expression of an unknown 32-kDa glycoprotein containing the alpha2,8-Sia glycotope. The mechanism for the increase in glycoprotein in inflamed mouse serum remains to be examined, as mRNA expression for all of the alpha2,8-sialyltransferases (ST8Sia I-VI) was unchanged during inflammation.Keywords:
Sialyltransferase
Sialoglycoproteins
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Abstract Sialic acid sugars that terminate cell‐surface glycans form the ligands for the sialic acid binding immunoglobulin‐like lectin (Siglec) family, which are immunomodulatory receptors expressed by immune cells. Interactions between sialic acid and Siglecs regulate the immune system, and aberrations contribute to pathologies like autoimmunity and cancer. Sialic acid/Siglec interactions between living cells are difficult to study owing to a lack of specific tools. Here, we report a glycoengineering approach to remodel the sialic acids of living cells and their binding to Siglecs. Using bioorthogonal chemistry, a library of cells with more than sixty different sialic acid modifications was generated that showed dramatically increased binding toward the different Siglec family members. Rational design reduced cross‐reactivity and led to the discovery of three selective Siglec‐5/14 ligands. Furthermore, glycoengineered cells carrying sialic acid ligands for Siglec‐3 dampened the activation of Siglec‐3 + monocytic cells through the NF‐κB and IRF pathways.
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Abstract Siglec-8, a lectin involved in the suppression of allergic responses, is considered a therapeutic target for developing glycan materials that enable the regulation of inflammatory diseases. In developing such glycan materials, the “multivalent effect” is essential for regulating immune responses. The “multivalent effect” dramatically increases the apparent affinities (avidities) of glycan-lectin interactions by clustering the glycan ligand multivalently. Numerous lectin-glycan interactions utilize this effect in immunological reactions, and Siglec-8 is thought to show an effect similar to those of other lectins. However, we hypothesized that increasing the local concentration of glycan ligands and modulating the glycan density are essential in allowing glycan ligands to interact effectively with Siglec-8. Here, we investigate the density-dependent changes in avidities between Siglec-8 and sialyl sulfo-oligosaccharides with a quartz crystal microbalance (QCM) for the first time. As a result, it was determined that Siglec-8 has an optimal glycan density (~9.2 × 10 2 molecules μm −2 ) for preferred interactions. Additionally, this suggests that the regulation of glycan density is key to developing therapeutic materials targeting Siglec-8. The results described here will promote the development of glycan materials that ameliorate immune disorders such as inflammation and anaphylaxis.
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Sialylation and sialic acid linkage in N-glycans are markers of disease but are analytically challenging to quantify. A capillary electrophoresis method is reported that integrates a unique combination of enzymes and lectins to modify sialylated N-glycans in real time in the capillary so that N-glycan structures containing α2–6-linked sialic acid are easily separated, detected, and quantified. In this study, N-glycans were sequentially cleaved by enzymes at the head of the separation capillary so that the presence of α2–6-linked sialic acids corresponded to a shift in the analyte migration time in a manner that enabled interpretation of the N-glycan structure. Following injection, only afucosylated N-glycan structures were passed through enzyme zones that contained α2–3 sialidase, followed by β1–3,4 galactosidase, which cleaved any terminal α2–3-linked sialic acid and underlying galactose yielding a terminal N-acetyl glucosamine. With this treatment complete, a third zone of α2–3,6,8 sialidase converted the remaining α2–6-linked sialic acid to terminal galactose. With these enzyme processing steps the α2–6-linked sialic acid residues on an N-glycan correlated directly to the number of terminal galactose residues that remained. The number of terminal galactose residues could be interpreted as a stepwise decrease in the migration time. Complex N-glycans from α-1-acid glycoprotein were analyzed using this approach, revealing that a limited number of α2–6-linked sialic acids were present with biantennary, triantennary, and tetraantennary N-glycans of α-1-acid glycoprotein generally containing 0 or 1 α2–6-linked sialic acid.
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The sialic acid content of erythrocytes of three different AB0 blood groups have been studied. The sialic acid contents of erythrocyte membranes containing 300 mg protein were determined and compared. Groups 0 (Rhesus negative), AB (both Rhesus negative and positive), and B (Rhesus negative) blood differed significantly (p less than 0.05) in total sialic acid content and in the distribution of sialic acid between sialoglycoproteins and other membrane components. Membrane materials containing 300 mg total protein showed sialic acid contents of 52.73 +/- 2.2 mumol sialic acid for group 0 (Rhesus negative) 34.77 +/- 1.16 mumol for group AB (Rh negative), 32.88 +/- 1.52 mumol for AB (Rh positive) and 21.23 +/- 0.84 mumol for B (Rh negative). In group 0 (Rh. neg.) membranes 39.4 +/- 1.4% of the total sialic acid was associated with the sialoglycoproteins. The percentage of sialic acids associated with sialoglycoproteins in other erythrocyte membranes were 77.7 +/- 1.3% for group B, and 55.6 +/- 1.0% and 56.4 +/- 1.8% for group AB (Rh. negative) and (Rh. positive) respectively. The changes appear to be independent of the Rhesus grouping but dependent on the AB0 grouping since membranes of the two Rhesus types of group AB had identical total sialic acid and sialoglycoproteins sialic acids. The sialic acid densities in sialoglycoproteins also differed from one erythrocyte type to another. Group 0 (Rh. negative) membrane sialoglycoproteins had sialic acid density of 140.5 +/- 3.1 nmol/mg compared to 71.7 +/- 1.2 nmol/mg for group B and 128.1 +/- 2.2 and 124.5 +/- 4.0 nmol/mg for group AB Rhesus negative and Rhesus positive respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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OBJECTIVE: Altered glycosylation of glycoconjugates is among the important molecular changes that accompany malignant transformation. The aim of our study was to investigate clinical usefulness of circulatory levels of sialic acid, sialoproteins and sialyltransferase for early diagnosis and management of oral cavity cancer (OC) patients. MATERIALS AND METHODS: Blood samples collected from 210 untreated OC patients, 100 patients with oral precancerous conditions (OPC) and 100 healthy males. OC patients were followed after initiation of anticancer treatment and 394 follow‐up samples were also collected. Serum sialic acid levels were measured spectrophotometrically. Sialyltransferase activity was analysed using radioassay. α 2‐6 sialoproteins were isolated using lectin affinity chromatography. RESULTS: Serum levels of free, protein bound and total sialic acid as well as their ratio with total proteins were significantly elevated in untreated OC patients compared with healthy individuals, patients with OPC as well as complete responders (CR). Levels of the markers were comparable between untreated OC patients and non‐responders. We observed positive correlation between serum levels of the markers and extent of malignant disease. Serum sialyltransferase activity showed significant elevations in OC patients compared with the controls ( P <0.001), patients with OPC ( P <0.05) and CR ( P <0.05). Higher sialic acid levels in OC patients at the time of diagnosis showed poor survival. The changes in serum proteins with terminal α 2‐6 sialic acid correlated well with the alterations in the levels of sialic acid forms and sialyltransferase activity. CONCLUSION: Our results confirmed the elevations in sialic acid and sialyltransferase levels in OC patients and suggested potential utility of these parameters in prognostication and treatment monitoring of this neoplasm. The alterations in these parameters in circulation were in accordance with the changes in α 2‐6 sialylated proteins.
Sialyltransferase
Glycoconjugate
N-Acetylneuraminic acid
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Sialoglycoproteins
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Soybean agglutinin
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