Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation.
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.
Gahring
L
L
Geriatric Research Education and Clinical Center, Salt Lake City Veterans Affairs Medical Center and University of Utah School of Medicine, Salt Lake City, Utah, 84112, USA.
Carlson
N G
NG
Meyer
E L
EL
Rogers
S W
SW
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D004660:Encephalitis / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D053804:Granzymes; D006801:Humans; D006868:Hydrolysis; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D014162:Transfection
D001324:Autoantigens; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; C104723:glutamate receptor ionotropic, AMPA 3; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases