Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation.

Abstract	Autoimmune processes are initiated when tolerance to self-proteins fails to be established or maintained and immune cells are stimulated by self-Ags. Although intracellular autoantigens are common, the origin of extracellular autoantigens is poorly defined and possibly more dangerous. In this study, we considered a mechanism for the origin of an extracellular autoantigen from the neuronal glutamate receptor subunit 3 (GluR3) in Rasmussen's encephalitis, a severe form of pediatric epilepsy. We demonstrate that specific cleavage of GluR3 by granzyme B (GB), a serine protease released by activated immune cells, can generate the GluR3B autoantigenic peptide, but only if an internal N:-linked glycosylation sequon within the GluR3-GB recognition sequence (ISND*S) is not glycosylated. However, this N:-glycon sequon while glycosylated normally is inefficiently used and glycosylation can fail. These results suggest that GB/N:-glycon sites may escape normal tolerance mechanisms and contribute to autoantibody-mediated immune diseases.
Authors	L Gahring, N G Carlson, E L Meyer, S W Rogers
Journal	Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 166 Issue 3 Pg. 1433-8 (Feb 01 2001) ISSN: 0022-1767 [Print] United States
PMID	11160179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References	Autoantigens Receptors, AMPA Recombinant Fusion Proteins glutamate receptor ionotropic, AMPA 3 GZMB protein, human Granzymes Gzmb protein, mouse Serine Endopeptidases
Topics	Amino Acid Sequence Animals Autoantigens (metabolism) Cell Line Cells, Cultured Cerebral Cortex (enzymology, immunology, metabolism) Encephalitis (enzymology, immunology, metabolism) Glycosylation Granzymes Humans Hydrolysis Immunity, Innate Mice Mice, Inbred C57BL Molecular Sequence Data Mutagenesis, Site-Directed Neurons (enzymology, immunology, metabolism) Receptors, AMPA (biosynthesis, genetics, metabolism) Recombinant Fusion Proteins (genetics, metabolism) Serine Endopeptidases (metabolism) Transfection

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