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,
* Department of Chemistry and
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720;
Howard Hughes Medical Institute, San Francisco, CA 94143;
Blood Systems Research Institute, San Francisco, CA 94118 and Department of Laboratory Medicine, University of California, San Francisco, CA 94121;
¶ Department of Biochemistry and Molecular Medicine, School of Medicine and the
|| Comparative Pathology Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616; and
# Abteilung Zelluläre Chemie, Zentrum Biochemie, Medizinische Hochschule Hannover, Germany
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The research was made possible by a grant from the California Institute for Regenerative Medicine (CIRM, Grant RS1-00365). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of CIRM or any other agency of the State of California.
P.M.D. conceived and helped to perform and analyze all experiments. J.K.N. conducted immunoblotting and in vivo immunoassays. C.M.S. and K.P.K.G. executed in vivo immunoassays. P.V.C. performed 5'FU assays and flow cytometric analyses of peripheral myeloid cells. M.O.M. designed and executed in vitro colony-forming assays. D.N. and F.A.T. performed the DP analysis. J.R.R. provided pathological evaluation of ear sections. P.G. prepared and analyzed human NK cells. B.W. and R.G.-S. provided transgenic mice, mAb 735, and endoneuraminidase N. P.M.D. and C.R.B. wrote the manuscript.
2 Address correspondence and reprint requests to Dr. Carolyn R. Bertozzi, Department of Chemistry, B84 Hildebrand Hall No. 1460, University of California, Berkeley, CA 94720. E-mail address: crb{at}berkeley.edu
3 Abbreviations used in this paper: polySia, polysialic acid; CHS, contact hypersensitivity; DL1, Delta-like-1; DNFB, 2,4-dinitrofluorobenzene; DP, degree of polymerization; Endo N, endoneuraminidase N; 5-FU, 5-fluorouracil; GAG, glycosaminoglycan; NANA, N-acetyl neuraminic acid; NCAM, neural cell adhesion molecule; rh, recombinant human.
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  T. J. Morley, L. M. Willis, C. Whitfield, W. W. Wakarchuk, and S. G. Withers A New Sialidase Mechanism: BACTERIOPHAGE K1F ENDO-SIALIDASE IS AN INVERTING GLYCOSIDASE J. Biol. Chem., June 26, 2009; 284(26): 17404 - 17410. [Abstract] [Full Text] [PDF]
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