Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies
| Autor: | Catherine Faivre-Sarrailh, Isabel Illa, Marilyne Labasque, Bruno Hivert, Gisela Nogales-Gadea, Luis Querol |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Glycosylation
Enzyme-Linked Immunosorbent Assay CHO Cells Immunoglobulin domain Biology medicine.disease_cause Biochemistry Autoimmunity Mice Myelin Cricetulus Neurobiology Neuroinflammation Contactins Polysaccharides Cell Line Tumor medicine Cell Adhesion Animals Humans Nerve Growth Factors Cell adhesion Molecular Biology Autoantibodies Glycoproteins Cell adhesion molecule Cell Membrane HEK 293 cells Autoantibody Peripheral Nervous System Diseases Cell Biology Molecular biology Cell aggregation Protein Structure Tertiary Rats Cell biology HEK293 Cells medicine.anatomical_structure nervous system Microscopy Fluorescence Mutation Cell Surface Protein Glycoprotein Cell Adhesion Molecules Protein Binding |
| Zdroj: | JOURNAL OF BIOLOGICAL CHEMISTRY r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau instname |
| ISSN: | 0021-9258 |
| Popis: | Background: The glycoproteins contactin and neurofascin-155 are implicated in axo-glial junctions insulating the node of Ranvier. Results:N-Glycosylated contactin is targeted in inflammatory neuropathy. Conclusion: Autoantibodies reveal specific N-glycans that are implicated in adhesive interaction between contactin and neurofascin-155. Significance: Autoantibodies against N-glycosylated contactin may be pathogenic via functional blocking. Cell adhesion molecules (CAMs) play a crucial role in the formation of the nodes of Ranvier and in the rapid propagation of the nerve impulses along myelinated axons. These CAMs are the targets of autoimmunity in inflammatory neuropathies. We recently showed that a subgroup of patients with aggressive chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shows autoantibodies to contactin (1). The complex of contactinCasprneurofascin-155 (NF155) enables the formation of paranodal junctions, suggesting that antibody attack against paranodes may participate in the severity of CIDP. In the present study, we mapped the molecular determinants of contactin targeted by the autoantibodies. In three patients, immunoreactivity was directed against the Ig domains of contactin and was dependent on N-glycans. The serum of one patient was selectively directed against contactin bearing mannose-rich N-glycans. Strikingly, the oligomannose type sugars of contactin are required for association with its glial partner NF155 (2). To investigate precisely the role of contactin N-glycans, we have mutated each of the nine consensus N-glycosylation sites independently. We found that the mutation of three sites (N467Q/N473Q/N494Q) in Ig domain 5 of contactin prevented soluble NF155-Fc binding. In contrast, these mutations did not abolish cis-association with Caspr. Next, we showed that the cluster of N-glycosylation sites (Asn-467, Asn-473, and Asn-494) was required for immunoreactivity in one patient. Using cell aggregation assays, we showed that the IgGs from the four CIDP patients prevented adhesive interaction between contactinCaspr and NF155. Importantly, we showed that the anti-contactin autoantibodies induced alteration of paranodal junctions in myelinated neuronal culture. These results strongly suggest that antibodies to CAMs may be pathogenic and induce demyelination via functional blocking activity. |
| Databáze: | OpenAIRE |
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