Rapid Trimming of Cell Surface Polysialic Acid (PolySia) by Exovesicular Sialidase Triggers Release of Preexisting Surface Neurotrophin

• Published in: The Journal of biological chemistry Vol. 290; no. 21; pp. 13202 - 13214
• Main Authors: Sumida, Mizuki, Hane, Masaya, Yabe, Uichiro, Shimoda, Yasushi, Pearce, Oliver M.T., Kiso, Makoto, Miyagi, Taeko, Sawada, Makoto, Varki, Ajit, Kitajima, Ken, Sato, Chihiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.05.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Animals, Newborn; Blotting, Western; Brain-derived Neurotrophic Factor (BDNF); Brain-Derived Neurotrophic Factor - metabolism; Cell Membrane - metabolism; Cells, Cultured; Exosome; Extracellular Matrix - enzymology; Fluorescent Antibody Technique; Glycobiology and Extracellular Matrices; Glycocalyx - metabolism; Membrane Microdomains - metabolism; Mice; Mice, Inbred C57BL; Microglia; Microglia - cytology; Microglia - metabolism; N-Glycolyneuraminic Acid; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Neuraminidase - genetics; Neuraminidase - metabolism; Oxygen - metabolism; Polysialic Acid; Polysialyltransferase; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sialic Acid; Sialic Acids - metabolism; Sialidase; Sialic Acid; Polysialyltransferase; N-Glycolyneuraminic Acid; Polysialic Acid; Exosome; Brain-derived Neurotrophic Factor (BDNF); Sialidase; Microglia
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.638759

As acidic glycocalyx on primary mouse microglial cells and a mouse microglial cell line Ra2, expression of polysialic acid (polySia/PSA), a polymer of the sialic acid Neu5Ac (N-acetylneuraminic acid), was demonstrated. PolySia is known to modulate cell adhesion, migration, and localization of neurotrophins mainly on neural cells. PolySia on Ra2 cells disappeared very rapidly after an inflammatory stimulus. Results of knockdown and inhibitor studies indicated that rapid surface clearance of polySia was achieved by secretion of endogenous sialidase Neu1 as an exovesicular component. Neu1-mediated polySia turnover was accompanied by the release of brain-derived neurotrophic factor normally retained by polySia molecules. Introduction of a single oxygen atom change into polySia by exogenous feeding of the non-neural sialic acid Neu5Gc (N-glycolylneuraminic acid) caused resistance to Neu1-induced polySia turnover and also inhibited the associated release of brain-derived neurotrophic factor. These results indicate the importance of rapid turnover of the polySia glycocalyx by exovesicular sialidases in neurotrophin regulation. Background: Although polySia is known to retain neurotrophins, their releasing mechanism remains unknown. Results: PolySia present on the cell surface of microglia is rapidly cleared by Neu1 sialidase on exovesicles secreted upon inflammatory stimulus, leading to neurotrophin release. Conclusion: Exovesicular Neu1 regulates rapid turnover of polySia and concomitant neurotrophin function. Significance: First demonstration of on-site turnover of polySia and its physiological significance.