Polysialic Acid, a Glycan with Highly Restricted Expression, Is Found on Human and Murine Leukocytes and Modulates Immune Responses

Department of Chemistry, University of California, Berkeley, CA 94720, USA.
The Journal of Immunology (Impact Factor: 4.92). 12/2008; 181(10):6850-8. DOI: 10.4049/jimmunol.181.10.6850
Source: PubMed


Polysialic acid (polySia) is a large glycan with restricted expression, typically found attached to the protein scaffold neural cell adhesion molecule (NCAM). PolySia is best known for its proposed role in modulating neuronal development. Its presence and potential functions outside the nervous systems are essentially unexplored. Herein we show the expression of polySia on hematopoietic progenitor cells, and demonstrate a role for this glycan in immune response using both acute inflammatory and tumor models. Specifically, we found that human NK cells modulate expression of NCAM and the degree of polymerization of its polySia glycans according to activation state. This contrasts with the mouse, where polySia and NCAM expression are restricted to multipotent hematopoietic progenitors and cells developing along a myeloid lineage. Sialyltransferase 8Sia IV(-/-) mice, which lacked polySia expression in the immune compartment, demonstrated an increased contact hypersensitivity response and decreased control of tumor growth as compared with wild-type animals. This is the first demonstration of polySia expression and regulation on myeloid cells, and the results in animal models suggest a role for polySia in immune regulation.

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    • "lactones, thus rendering the Sia chemically neutral (Troy 1992, 1995; Zanetta et al. 2001; Angata and Varki 2002; Schnaar et al. 2014). A less frequent form of sialylated glycans is those containing extended chains of di-, tri-, oligo-and polySia with degrees of polymerization (DP) extending to over 400 Sia residues when determined under nonhydrolytic conditions (Iwasaki et al. 1990; Sato et al. 2000; Nakata and Troy 2005; Drake et al. 2008; Kanato et al. 2008; Sato and Kitajima 2013). KDN was first discovered in the cortical alveolar polysialoglycoprotein of rainbow trout eggs (Nadano et al. 1986). "
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    ABSTRACT: An elevated level of the free deaminated Sia, KDN, was first discovered in human ovarian cancers (OC), suggesting that KDN may be an oncodevelopmental antigen (Inoue et al. 1998). To determine if this unexpected finding was unique to OC, we developed a LC-MS/MS glycomic approach to quantitatively determine the level of free and conjugated forms of KDN, Neu5Ac and Neu5Gc in head and neck cancers of the throat, and in a sub-population of matched lymph nodes. These findings were correlated with tumor (T), nodal (N), metastatic (M) involvement, and the differentiation status of the tumors. The following new findings are reported: (1) The level of free KDN in 49 throat cancers and a sub-population of 10 regional lymph nodes accounted for 94.5% and 93.3% respectively, of the total level of KDN (∼2 µg/g); (2) In marked contrast, the level of free Neu5Ac in throat cancer and lymph nodes accounted for only 6.5% and 5.1% of the total level of Neu5Ac (85 µ/g); (3) The level of Neu5Gc (0.03 µ/g) in throat cancers was 0.30% of the level of Neu5Ac, 2/3 was conjugated and 1/3 free. The central importance of these new findings is that the elevated level of free KDN relative to free Neu5Ac and Neu5GC in throat cancers showing no lymphatic metastasis, and which are poorly to moderately differentiated, suggests that free KDN may be useful as a biomarker for detecting some early-stage cancers at biopsy, and be of possible prognostic value in determining the potential degree of malignancy. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:
    Glycobiology 07/2015; 25(12). DOI:10.1093/glycob/cwv051 · 3.15 Impact Factor
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    • "A small subset of CD56 expressed in myeloid cells in murine bone marrow is polysialylated Although it was previously reported that CD56 is polysialylated in murine BM leukocytes (Drake et al. 2008), the polysialylated protein described in that study had a much smaller molecular weight (140 kDa) than the predominant 270 kDa polysialylated protein detected in our analysis (Figure 1), and the specific types of myeloid cells modified by polySia were not specified. We first identified the BM leukocytes that express CD56 and then evaluated whether CD56 in these cells is the 270 kDa polysialylated protein seen in Figure 1 using two methods; namely, by assessing the mobility shift of CD56 on immunoblot after treating cells with endoN and by analyzing the expression of polySia on the surface of BM leukocytes of NCAM − / − mice. "
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    ABSTRACT: Polysialic acid (polySia) is a unique linear homopolymer of α2,8-linked sialic acid that has been studied extensively as a posttranslational modification of neural cell adhesion molecule (NCAM/CD56) in the central nervous system. Only two proteins are known to be polysialylated in cells of the immune system: CD56 on human natural killer cells and murine bone marrow (BM) leukocytes, and neuropilin-2 (NRP-2) on dendritic cells (DC). We tested the hypothesis that polySia expression is regulated during maturation and migration of leukocytes and plays a role in functional activity. Using wild type and NCAM(-/-) mice, we show that BM neutrophils express only polysialylated CD56, whereas a subset of BM monocytes expresses polysialylated CD56 and/or another polysialylated protein(s). We demonstrate that polysialylated CD56 expression is progressively down-regulated in wild type monocytes and monocyte-derived cells during migration from BM through peripheral blood (PB) to pulmonary and peritoneal sites of inflammation. Freshly-isolated monocyte-derived peritoneal macrophages are devoid of polySia yet reexpress polySia on NRP-2 and an additional protein(s) after maintenance in culture. Removal of polySia from these cells enhances phagocytosis of Klebsiella pneumoniae, suggesting that down-regulation of polySia on macrophages facilitates bacterial clearance. Using wild type and NRP-2(-/-) mice, we demonstrate that NRP-2 and an additional protein(s) are polysialylated by ST8 SiaIV in BM-derived DCs. We conclude that polySia expression in monocyte-derived cells is dynamically regulated by ST8 SiaIV activity and by expression of carrier proteins during recruitment to sites of inflammation and influences cellular interactions with microbes, contributing to innate and adaptive immune responses.
    Glycobiology 05/2014; 24(9). DOI:10.1093/glycob/cwu050 · 3.15 Impact Factor
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    • "Polysialic acid is a large glycan with restricted expression, typically found to be attached to the protein scaffold neural cell adhesion molecule (NCAM). Polysialylated NCAM, which is found in various types of cancer, including gliomas, is positively associated with metastasis and disease progression (21). β4GalT5 could effectively galactosylate the GlcNAcβ1–6 branch which is a marker of glioma. "
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    ABSTRACT: Changes in glycosylation due to specific alterations of glycosyltransferase activity have been shown in various tumor cells, including human glioma cells. β1,3-N‑acetylglucosaminyltransferase-8 (β3GnT8) catalyzes the formation of polylactosamine on β1-6 branched N-glycans. Upregulated expression of β3GnT8 was described in some tumors, but its precise role in regulating glioma invasion and metastasis remains unclear. In this study, we report on an investigation of the expression of β3GnT8 in human glioma by immunohistochemical analysis. Out of 42 glioma tissues, 37 (88.1%) showed positive β3GnT8 expression, which was significantly higher than that in normal brain tissues (P<0.001). Additionally, the level of β3GnT8 increased with increased pathological grade of gliomas. Silencing of β3GnT8 in U251 glioma cells attenuated the formation of polylactosamine, and decreased cell proliferation, migration and metastatic ability in vitro and in vivo. By contrast, the overexpression of β3GnT8 in U251 cells exhibited enhanced metastatic potential. A positive correlation between β3GnT8 and matrix metalloproteinase-2 (MMP-2) expression in U251 cells was also observed. The results demonstrated a critical role of β3GnT8 in the metastatic potential of glioma cells, indicating that manipulating β3GnT8 expression may have therapeutic potential for the treatment of malignant glioma.
    International Journal of Molecular Medicine 04/2014; 33(6). DOI:10.3892/ijmm.2014.1736 · 2.09 Impact Factor
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