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Patients’ IgLON5 autoantibodies interfere with IgLON5-protein interactions

BACKGROUND: Anti-IgLON5 disease is a rare neurological disorder characterized by autoantibodies against IgLON5, and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule but its physiological function is unknown. Our aim was to investigate the IgLON5 interactome and to deter...

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Autores principales: Landa, Jon, Serafim, Ana Beatriz, Gaig, Carles, Saiz, Albert, Koneczny, Inga, Hoftberger, Romana, Santamaria, Joan, Dalmau, Josep, Graus, Francesc, Sabater, Lidia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10073962/
https://www.ncbi.nlm.nih.gov/pubmed/37033996
http://dx.doi.org/10.3389/fimmu.2023.1151574
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author Landa, Jon
Serafim, Ana Beatriz
Gaig, Carles
Saiz, Albert
Koneczny, Inga
Hoftberger, Romana
Santamaria, Joan
Dalmau, Josep
Graus, Francesc
Sabater, Lidia
author_facet Landa, Jon
Serafim, Ana Beatriz
Gaig, Carles
Saiz, Albert
Koneczny, Inga
Hoftberger, Romana
Santamaria, Joan
Dalmau, Josep
Graus, Francesc
Sabater, Lidia
author_sort Landa, Jon
collection PubMed
description BACKGROUND: Anti-IgLON5 disease is a rare neurological disorder characterized by autoantibodies against IgLON5, and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule but its physiological function is unknown. Our aim was to investigate the IgLON5 interactome and to determine if IgLON5 antibodies (IgLON5-abs) affect these protein interactions. METHODS: IgLON5 interactome was investigated by mass spectrometry sequencing of proteins immunoprecipitated by IgLON5 autoantibodies using cultures of rat cerebellar granular neurons (CGNs). Shedding of IgLON5 was explored using HEK cells transfected with human IgLON5 plasmid and in CGNs. Interactions of IgLON5 with identified binding partners and IgLON5-abs effects were confirmed by immunofluorescence in transfected HEK cells and rat hippocampal neurons. RESULTS: Patients’ IgLON5 antibodies co-precipitated all members of the IgLON family and three 3 additional surface proteins. IgLON5 predominantly establishes homomeric and heteromeric cis (within the cell) and trans (between cells)-interactions with other IgLON family members and undergoes spontaneous ectodomain shedding. Antibodies from patients with anti-IgLON5 disease prevent trans-interactions in hippocampal neurons independently of the IgLON5 IgG subclass distribution. CONCLUSIONS: We show a potentially novel pathogenic mechanism of IgLON5-abs that consists in blocking IgLON5 interactions with its binding partners. These findings extend our knowledge about the physiological role of IgLON5 and pave the way to future understanding of the pathological mechanisms of anti-IgLON5 disease.
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spelling pubmed-100739622023-04-06 Patients’ IgLON5 autoantibodies interfere with IgLON5-protein interactions Landa, Jon Serafim, Ana Beatriz Gaig, Carles Saiz, Albert Koneczny, Inga Hoftberger, Romana Santamaria, Joan Dalmau, Josep Graus, Francesc Sabater, Lidia Front Immunol Immunology BACKGROUND: Anti-IgLON5 disease is a rare neurological disorder characterized by autoantibodies against IgLON5, and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule but its physiological function is unknown. Our aim was to investigate the IgLON5 interactome and to determine if IgLON5 antibodies (IgLON5-abs) affect these protein interactions. METHODS: IgLON5 interactome was investigated by mass spectrometry sequencing of proteins immunoprecipitated by IgLON5 autoantibodies using cultures of rat cerebellar granular neurons (CGNs). Shedding of IgLON5 was explored using HEK cells transfected with human IgLON5 plasmid and in CGNs. Interactions of IgLON5 with identified binding partners and IgLON5-abs effects were confirmed by immunofluorescence in transfected HEK cells and rat hippocampal neurons. RESULTS: Patients’ IgLON5 antibodies co-precipitated all members of the IgLON family and three 3 additional surface proteins. IgLON5 predominantly establishes homomeric and heteromeric cis (within the cell) and trans (between cells)-interactions with other IgLON family members and undergoes spontaneous ectodomain shedding. Antibodies from patients with anti-IgLON5 disease prevent trans-interactions in hippocampal neurons independently of the IgLON5 IgG subclass distribution. CONCLUSIONS: We show a potentially novel pathogenic mechanism of IgLON5-abs that consists in blocking IgLON5 interactions with its binding partners. These findings extend our knowledge about the physiological role of IgLON5 and pave the way to future understanding of the pathological mechanisms of anti-IgLON5 disease. Frontiers Media S.A. 2023-03-21 /pmc/articles/PMC10073962/ /pubmed/37033996 http://dx.doi.org/10.3389/fimmu.2023.1151574 Text en Copyright © 2023 Landa, Serafim, Gaig, Saiz, Koneczny, Hoftberger, Santamaria, Dalmau, Graus and Sabater https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Landa, Jon
Serafim, Ana Beatriz
Gaig, Carles
Saiz, Albert
Koneczny, Inga
Hoftberger, Romana
Santamaria, Joan
Dalmau, Josep
Graus, Francesc
Sabater, Lidia
Patients’ IgLON5 autoantibodies interfere with IgLON5-protein interactions
title Patients’ IgLON5 autoantibodies interfere with IgLON5-protein interactions
title_full Patients’ IgLON5 autoantibodies interfere with IgLON5-protein interactions
title_fullStr Patients’ IgLON5 autoantibodies interfere with IgLON5-protein interactions
title_full_unstemmed Patients’ IgLON5 autoantibodies interfere with IgLON5-protein interactions
title_short Patients’ IgLON5 autoantibodies interfere with IgLON5-protein interactions
title_sort patients’ iglon5 autoantibodies interfere with iglon5-protein interactions
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10073962/
https://www.ncbi.nlm.nih.gov/pubmed/37033996
http://dx.doi.org/10.3389/fimmu.2023.1151574
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