Sialic acid O-acetylation: From biosynthesis to roles in health and disease

Visser, Eline A.; Moons, Sam J; Timmermans, Suzanne B. P. E.; Jong, Heleen de; Boltje, Thomas J.; Büll, Christian

doi:10.1016/j.jbc.2021.100906

Cited by 56 publications

(53 citation statements)

References 253 publications

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“…fucosylation and branching), 21,22 as well as post-glycosylation modification (e.g. acetylation and sulfation), 23,24 can significantly impact the affinity of glycans for Siglecs. 25,26 Moreover, the context in which these glycans are presented has also shown to play a role, such as the specific protein to which the glycans are attached and the density of presented glycans on the polypeptide backbone as in the case of O-glycans appended to mucins.…”

Section: Introductionmentioning

confidence: 99%

Carbohydrate sulfation as a mechanism for fine-tuning Siglec ligands

Jung

Enterina

Bui

et al. 2021

Preprint

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The immunomodulatory family of Siglecs recognize sialic acid-containing glycans as self, which is exploited in cancer for immune-evasion. The biochemical nature of Siglec ligands remains incompletely understood with emerging evidence suggesting the importance of carbohydrate sulfation. Here, we investigate how specific sulfate modifications affect Siglec ligands by overexpressing eight carbohydrate sulfotransferases (CHSTs) in five cell lines. Overexpression of three CHSTs (CHST1, CHST2, or CHST4) significantly enhances the binding of numerous Siglecs. Unexpectedly, two other CHSTs (Gal3ST2 and Gal3ST3) diminish Siglec binding, suggesting a new mode to modulate Siglec ligands via sulfation. Results are cell type dependent, indicating that the context in which sulfated glycans are presented is important. Moreover, pharmacological blockade of N- and O-glycan maturation reveals a cell type-specific pattern of importance for either class of glycan. Production of a highly homogenous CD33 (Siglec-3) fragment enabled a mass spectrometry-based binding assay to determine 10-fold and 3-fold enhanced affinity for Neu5Acα2-3(6-O-sulfo)Galβ1-4GlcNAc and Neu5Acα2-3Galβ1-4(6-O-sulfo)GlcNAc, respectively, over Neu5Acα2-3Galβ1-4GlcNAc. CD33 showed significant additivity in affinity (36-fold) for the disulfated ligand, Neu5Acα2-3(6-O-sulfo)Galβ1-4(6-O-sulfo)GlcNAc. Moreover, overexpression of both CHST1 and CHST2 in cells greatly enhanced the binding of several Siglecs, including CD33. Finally, we reveal that CHST1 is upregulated in numerous cancers, correlating with poorer survival rates and sodium chlorate sensitivity for the binding of Siglecs to cancer cell lines. These results provide new insights into carbohydrate sulfation as a modification that is a general mechanism for tuning Siglec ligands on cells, including in cancer.

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Section: Introductionmentioning

confidence: 99%

Carbohydrate sulfation as a mechanism for fine-tuning Siglec ligands

Jung

Enterina

Bui

et al. 2021

Preprint

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“…In SARS-CoV-2 interactome with host receptors, SA component of membrane glycoproteins and of receptors is considered of utmost importance due to its ubiquitous location. This molecule represents a fundamental mediator of cell metabolism derangement in several chronic degenerative diseases 205,206 The primary event in COVID-19 infection is the attachment of the virus particle to the surface of the host cell, which is mediated also by sialylated cell surface receptors on several types of cells, mainly in the respiratory tract in humans. Viruses interacting with humans preferably show a α2,6 binding to host cell receptors.…”

Section: A) Sialic Acidmentioning

confidence: 99%

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

et al. 2022

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Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

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“…In addition, the diversity of Sia modifications, including sulfation, acetylation, and lactylation, is well known [ 7 ]. Evidence of the relationship between Sia modification and cancer has accumulated, but its biosynthetic pathways and functions remain largely unknown [ 13 ]. Sialoglycoconjugates are closely related to cancer; therefore, a comprehensive analysis of cancer cell-surface sialoglycoconjugates is needed to explore new biomarkers and therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Oligo/Polysialylglycoconjugates in Cancer Cell Lines

Hane

Kitajima

Sato

2022

IJMS

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In cancer cells, cell-surface sialylation is altered, including a change in oligo/polysialic acid (oligo/polySia) structures. Since they are unique and rarely expressed in normal cells, oligo/polySia structures may serve as promising novel biomarkers and targets for therapies. For the diagnosis and treatment of the disease, a precise understanding of the oligo/polySia structures in cancer cells is necessary. In this study, flow cytometric analysis and gene expression datasets were obtained from sixteen different cancer cell lines. These datasets demonstrated the ability to predict glycan structures and their sialylation status. Our results also revealed that sialylation patterns are unique to each cancer cell line. Thus, we can suggest promising combinations of antibody and cancer cell for glycan prediction. However, the precise prediction of minor glycans need to be further explored.

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Sialic acid O-acetylation: From biosynthesis to roles in health and disease

Cited by 56 publications

References 253 publications

Carbohydrate sulfation as a mechanism for fine-tuning Siglec ligands

Carbohydrate sulfation as a mechanism for fine-tuning Siglec ligands

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

Comprehensive Analysis of Oligo/Polysialylglycoconjugates in Cancer Cell Lines

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