Human Xeno-Autoantibodies against a Non-Human Sialic Acid Serve as Novel Serum Biomarkers and Immunotherapeutics in Cancer

Padler‐Karavani, Vered; Hurtado-Ziola, Nancy; Pu, Minya; Yu, Hai; Huang, Shengshu; Muthana, Saddam; Chokhawala, Harshal A.; Cao, Hongzhi; Secrest, Patrick; Friedmann‐Morvinski, Dinorah; Singer, Oded; Ghaderi, Darius; Verma, Inder M.; Liu, Yu Tsueng; Messer, Karen; Chen, Xi; Varki, Ajit; Schwab, Richard B.

doi:10.1158/0008-5472.can-10-4102

Cited by 125 publications

(208 citation statements)

References 46 publications

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“…Glycan 20, which is an ␣2-6 monosialylated derivative of NA2, bound RCA-I before and after neuraminidase, although binding was not enhanced after neuraminidase treatment. RCA-I bound weakly to ␣2-6-sialylated lactose and LNnT (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), unlike the corresponding ␣2-3-sialylated lactose and LNnT (41-57), which were not bound. Although most sialic acid derivatives moderately decreased RCA-I binding to NA2, ␣2-6-sialylation with Neu5Ac8Me (19) and Neu5Gc9Ac (25) greatly inhibit RCA-I binding.…”

Section: Resultsmentioning

confidence: 98%

“…Analyses of specific expression and functional rec-ognition of modified sialic acids have been difficult due to their unavailability. Previous development of sialoside arrays focused on sialosides containing four common natural sialic acid forms (Neu5Ac, Neu5Gc, Neu5Ac9Ac, and Neu5Gc9Ac) presented on diverse underlying glycans (17). An earlier chemoenzymatically synthesized biotinylated sialoside array with diverse sialic acid forms was presented on microplates without purification, which introduced some complexity to protein-binding studies (16).…”

Section: Discussionmentioning

confidence: 99%

“…in chemoenzymatic synthesis of sialosides containing natural and non-natural sialic acid residues using multiple promiscuous sialoside biosynthetic enzymes (5,(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

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A Sialylated Glycan Microarray Reveals Novel Interactions of Modified Sialic Acids with Proteins and Viruses

Song

Chen

et al. 2011

Journal of Biological Chemistry

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132

115

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Many glycan-binding proteins in animals and pathogens recognize sialic acid or its modified forms, but their molecular recognition is poorly understood. Here we describe studies on sialic acid recognition using a novel sialylated glycan microarray containing modified sialic acids presented on different glycan backbones. Glycans terminating in ␤-linked galactose at the nonreducing end and with an alkylamine-containing fluorophore at the reducing end were sialylated by a one-pot three-enzyme system to generate ␣2-3-and ␣2-6-linked sialyl glycans with 16 modified sialic acids. The resulting 77 sialyl glycans were purified and quantified, characterized by mass spectrometry, covalently printed on activated slides, and interrogated with a number of key sialic acid-binding proteins and viruses. Sialic acid recognition by the sialic acid-binding lectins Sambucus nigra agglutinin and Maackia amurensis lectin-I, which are routinely used for detecting ␣2-6-and ␣2-3-linked sialic acids, are affected by sialic acid modifications, and both lectins bind glycans terminating with 2-keto-3-deoxy-D-glycero-D-galactonononic acid (Kdn) and Kdn derivatives stronger than the derivatives of more common N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Three human parainfluenza viruses bind to glycans terminating with Neu5Ac or Neu5Gc and some of their derivatives but not to Kdn and its derivatives. Influenza A virus also does not bind glycans terminating in Kdn or Kdn derivatives. An especially novel aspect of human influenza A virus binding is its ability to equivalently recognize glycans terminated with either ␣2-6-linked Neu5Ac9Lt or ␣2-6-linked Neu5Ac. Our results demonstrate the utility of this sialylated glycan microarray to investigate the biological importance of modified sialic acids in protein-glycan interactions.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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A Sialylated Glycan Microarray Reveals Novel Interactions of Modified Sialic Acids with Proteins and Viruses

Song

Chen

et al. 2011

Journal of Biological Chemistry

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132

115

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“…In striking contrast, the human immune system regards Neu5Gc-containing glycan structures as "foreign," resulting in a polyclonal humoral response, with circulating and varying titers of anti-Neu5Gc antibodies among all humans (29,30). The incorporation of dietary Neu5Gc in the face of an ongoing immune response against this non-human epitope makes Neu5Gc the first known example of a "xeno-autoantigen" (31,32). Interestingly, the major sites of Neu5Gc accumulation in humans (endothelia of blood vessels and epithelia lining the hollow organs) are also the locations where predominantly human-specific diseases involving chronic inflammation seem to occur (31).…”

mentioning

confidence: 99%

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

Bergfeld

Pearce

Díaz

et al. 2012

Journal of Biological Chemistry

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Background: Pathways for turnover and degradation of the mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) are currently unknown. Results: Mammalian cells can degrade Neu5Gc by sequential conversion into N-glycolylmannosamine, N-glycolylglucosamine, and N-glycolylglucosamine 6-phosphate, following release of glycolate and glucosamine 6-phosphate. Conclusion: Basic N-acetylhexosamine pathways seem tolerant toward the N-glycolyl substituent. Significance: We elucidate the metabolic turnover of the diet-derived human xeno-autoantigen Neu5Gc.

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“…Neu5Gc, a nonhuman Sia, is abundantly present in malignant tissues 33 . The increase and metabolic incorporation of Neu5Gc are associated with inflammation within a mechanism of interaction with circulating anti-Neu5Gc antibodies [34][35][36][37] . Not only Neu5Ac and Neu5Gc increase in expression in malignant tissues, but KDN-containing N-glycan also accumulates in significant amounts in prostate cancer tissues 9 .…”

Section: Discussionmentioning

confidence: 99%

Level and distribution of secreted and cell-associated N-acetyl, N-glycolylneuraminic, and deaminoneuraminic acids in osteosarcoma cells isolated from patients

Phitak¹,

Klangjorhor²,

Pothacharoen³

et al. 2017

ScienceAsia

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Sialic acids, which are members of a family of 9-carbon carboxylated sugars, usually occupy the terminal position of the glycan chains of glycoconjugates and play an important role in various biological processes. Nacetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the dominant sialic acids in mammals, whereas deaminoneuraminic acids (KDN) can be detected in trace amounts. The increase of sialic acid levels has been reported in relation to the pathology and aggressiveness of cancer. Here we used a fluorometric-HPLC method to investigate the level and distribution of Neu5Ac, Neu5Gc, and KDN in osteosarcoma cells isolated from 7 patients and compare them with those in osteoblasts isolated from 3 patients with other bone diseases. Both cell types expressed all three sialic acids with abundances Neu5Ac > Neu5Gc > KDN. Total sialic acid levels in osteosarcoma cells were twice that in osteoblast cells. Only cell-associated Neu5Ac and Neu5Gc levels were higher, but not secreted forms. However, cell-associated and secreted KDN levels were not significantly different among those two groups. This suggests that the level and distribution of sialic acids in osteosarcoma cells were different from those in normal osteoblast cells. Thus their level, type, and distribution may be related to the pathology of osteosarcoma.

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Human Xeno-Autoantibodies against a Non-Human Sialic Acid Serve as Novel Serum Biomarkers and Immunotherapeutics in Cancer

Cited by 125 publications

References 46 publications

A Sialylated Glycan Microarray Reveals Novel Interactions of Modified Sialic Acids with Proteins and Viruses

A Sialylated Glycan Microarray Reveals Novel Interactions of Modified Sialic Acids with Proteins and Viruses

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

Level and distribution of secreted and cell-associated N-acetyl, N-glycolylneuraminic, and deaminoneuraminic acids in osteosarcoma cells isolated from patients

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