Platelets Support Extracellular Sialylation by Supplying the Sugar Donor Substrate

Lee, Melissa M.; Nasirikenari, Mehrab; Manhardt, Charles; Ashline, David J.; Hanneman, Andrew; Reinhold, Vernon N.; Lau, Joseph T.Y.

doi:10.1074/jbc.c113.546713

Cited by 63 publications

(59 citation statements)

References 34 publications

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“…Consistent with previous studies in which 104 pmol of CMP-SA per milligram of platelet granule extract was reported (22,25), we found that supernatants from activated, but not resting, platelets provided enough CMP-SA to add α2,6-linked sialic acids to target glycans when used in combination with rST6 (Fig. 7B).…”

Section: Platelets At Least Partially Supply the Nucleotide Sugar Donorsupporting

confidence: 81%

“…Interestingly, studies have revealed that the granules within platelets contain high concentrations of both glycosyltransferase enzymes, although not ST6Gal1 and nucleotide sugar donors, including CMP-SA (22,25). Indeed, granular concentration of CMP-SA is estimated to be 104 pmol/mg granule extract, suggesting that platelet activation and degranulation could be one source of circulatory CMP-SA.…”

Section: Discussionmentioning

confidence: 99%

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B-cell–independent sialylation of IgG

Jones

Oswald

Joshi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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IgG carrying terminal α2,6-linked sialic acids added to conserved N-glycans within the Fc domain by the sialyltransferase ST6Gal1 accounts for the anti-inflammatory effects of large-dose i.v. Ig (IVIg) in autoimmunity. Here, B-cell-specific ablation of ST6Gal1 in mice revealed that IgG sialylation can occur in the extracellular environment of the bloodstream independently of the B-cell secretory pathway. We also discovered that secreted ST6Gal1 is produced by cells lining central veins in the liver and that IgG sialylation is powered by serum-localized nucleotide sugar donor CMP-sialic acid that is at least partially derived from degranulating platelets. Thus, antibody-secreting cells do not exclusively control the sialylationdependent anti-inflammatory function of IgG. Rather, IgG sialylation can be regulated by the liver and platelets through the corresponding release of enzyme and sugar donor into the cardiovascular circulation.W hile en route to the plasma membrane as integral membrane proteins or for secretion, glycoproteins exiting the endoplasmic reticulum traverse the cis-, medial-, and trans-Golgi apparatus where the associated N-linked glycans are remodeled into their final form. This classically defined secretory pathway dictates that the glycoform of all glycoproteins produced by a cell is largely determined by the cohort of enzymes within the Golgi and the metabolic circumstances of that specific cell.Protein glycosylation is known to play fundamental roles in all aspects of biology, but has recently gained significant attention in immunology. When administered at high doses, i.v. Ig (IVIg) is an effective anti-inflammatory treatment for autoimmune patients (1). In 2006, it was discovered that the ∼10% of IgG molecules that carry α2,6-linked sialic acids upon the conserved biantennary N-glycans within the Fc domain provided the potent IVIg anti-inflammatory activity in autoimmune disease (2). Indeed, enrichment for the sialylated IgG (sIgG) fraction from IVIg pools increased the efficacy of treatment in mouse models of arthritis 100-fold in an IL-4-dependent fashion through receptors such as CD209 (DC-SIGN) (3, 4). Moreover, it was reported that sialylation of IgG also impacts antibody affinity maturation, although the mechanism underlying this phenomenon remains to be fully elucidated (5). These data indicate that sialylation serves as the mechanism underlying pleotropic IgG function (3,4,6).Epidemiologic analyses published since the reports cited above are consistent with this model. For example, female rheumatoid arthritis patients often go into remission during pregnancy and then relapse following childbirth. Analysis of sIgG levels before, during, and after pregnancy showed that the level of sIgG increases rapidly during pregnancy-induced remission, whereas during periods of exacerbated disease, sIgG is essentially undetectable (7,8). To date, it is unclear whether IgG sialylation patterns precede or result from the inflammatory state, and essentially nothing is known about the regulatory mecha...

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Section: Platelets At Least Partially Supply the Nucleotide Sugar Donorsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

B-cell–independent sialylation of IgG

Jones

Oswald

Joshi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

View full text Add to dashboard Cite

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“…A cell surface galactosyltransferase functions as a type IV collagen adhesion molecule and galactosylates type IV collagen (93). Platelets can supply sugar donor substrates for extracellular glycosylation (94). Collagen Hyl residues can also be phosphorylated (95), and phosphorylation of collagen can occur extracellularly (96).…”

Section: Discussionmentioning

confidence: 99%

Glycosylation Modulates Melanoma Cell α2β1 and α3β1 Integrin Interactions with Type IV Collagen

Stawikowski

Aukszi

Stawikowska

et al. 2014

Journal of Biological Chemistry

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“…Previously, we demonstrated that activated platelets are a functional source of CMP-Sia sugar-donor driving extrinsic sialylation (Lee et al 2014). Others have shown that platelets also contain a cache of other sugar precursor substrates, such as UDP-GalNAc, UDP-Gal, which is released into circulation upon platelet activation (Wandall et al 2012;Jones et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Second, circulating platelets have been implicated to be carriers of the activated sugar-donor substrates that can be released upon activation (Wandall et al 2012). We recently provided proof that activated platelets can supply activated sialic acid-donor substrate in sufficient concentration to efficiently drive extrinsic sialylation by ST6Gal-1 (Lee et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Circulating blood and platelets supply glycosyltransferases that enable extrinsic extracellular glycosylation

et al. 2016

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Glycosyltransferases, usually residing within the intracellular secretory apparatus, also circulate in the blood. Many of these blood-borne glycosyltransferases are associated with pathological states, including malignancies and inflammatory conditions. Despite the potential for dynamic modifications of glycans on distal cell surfaces and in the extracellular milieu, the glycan-modifying activities present in systemic circulation have not been systematically examined. Here, we describe an evaluation of blood-borne sialyl-, galactosyl-and fucosyltransferase activities that act upon the four common terminal glycan precursor motifs, GlcNAc monomer, Gal(β3)GlcNAc, Gal(β4)GlcNAc and Gal(β3)GalNAc, to produce more complex glycan structures. Data from radioisotope assays and detailed product analysis by sequential tandem mass spectrometry show that blood has the capacity to generate many of the well-recognized and important glycan motifs, including the Lewis, sialylLewis, H-and Sialyl-T antigens. While many of these glycosyltransferases are freely circulating in the plasma, human and mouse platelets are important carriers for others, including ST3Gal-1 and β4GalT. Platelets compartmentalize glycosyltransferases and release them upon activation. Human platelets are also carriers for large amounts of ST6Gal-1 and the α3-sialyl to Gal(β4)GlcNAc sialyltransferases, both of which are conspicuously absent in mouse platelets. This study highlights the capability of circulatory glycosyltransferases, which are dynamically controlled by platelet activation, to remodel cell surface glycans and alter cell behavior.

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Platelets Support Extracellular Sialylation by Supplying the Sugar Donor Substrate

Cited by 63 publications

References 34 publications

B-cell–independent sialylation of IgG

B-cell–independent sialylation of IgG

Glycosylation Modulates Melanoma Cell α2β1 and α3β1 Integrin Interactions with Type IV Collagen

Circulating blood and platelets supply glycosyltransferases that enable extrinsic extracellular glycosylation

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