Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines

Autophagy is a catabolic process involved in different cellular functions. However, the molecular pathways governing its potential roles in different cell types remain poorly understood. We investigated the role of autophagy in the context of proteotoxic stress in two central nervous system cell typ...

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Autores: Domínguez-Martín, Helena, Gavilán, Elena, Parrado, Celia, Burguillos, Miguel Ángel, Daza, Paula, Ruano, Diego
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/385680
Acesso em linha:http://hdl.handle.net/10261/385680
https://api.elsevier.com/content/abstract/scopus_id/85213341334
Access Level:acceso abierto
Palavra-chave:Proteotoxic stress
Autophagy
Microglia
Neurons
Phagocytosis
Proteasome
Proteostasis
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spelling Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell LinesDomínguez-Martín, HelenaGavilán, ElenaParrado, CeliaBurguillos, Miguel ÁngelDaza, PaulaRuano, DiegoProteotoxic stressAutophagyMicrogliaNeuronsPhagocytosisProteasomeProteostasisAutophagy is a catabolic process involved in different cellular functions. However, the molecular pathways governing its potential roles in different cell types remain poorly understood. We investigated the role of autophagy in the context of proteotoxic stress in two central nervous system cell types: the microglia-like cell line BV2 and the neuronal-like cell line N2a. Proteotoxic stress, induced by proteasome inhibition, produced early apoptosis in BV2 cells, due in part to a predominant activation of the PERK-CHOP pathway. In contrast, N2a cells showcased greater resistance and robust induction of the IRE1α-sXbp1 arm of the UPR. We also demonstrated that proteotoxic stress activated autophagy in both cell lines but with different kinetics and cellular functions. In N2a cells, autophagy restored cellular proteostasis, while in BV2 cells, it participated in regulating phagocytosis. Finally, proteotoxic stress predominantly activated the mTORC2-AKT-FOXO1-β-catenin pathway in BV2 cells, while N2a cells preferentially induced the PDK1-AKT-FOXO3 axis. Collectively, our findings suggest that proteotoxic stress triggers cell-specific responses in microglia and neurons, with different physiological outcomes.This work was supported by grants from the Junta de Andalucía to the research group CTS257-Aging and Neurodegeneration for D.R. Also by CNS2022-135867 funded by MICIU/AEI/10.13039/501100011033, by the European Union NextGenerationEU/PRTR and PID2022-136485OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER, UE for M.A.B.Peer reviewedMultidisciplinary Digital Publishing InstituteJunta de AndalucíaMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)European CommissionGavilán, Elena [0000-0002-8173-2638]Burguillos, Miguel Ángel [0000-0002-3165-9997]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/385680https://api.elsevier.com/content/abstract/scopus_id/85213341334reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136485OB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/cells13242069https://doi.org/10.3390/cells13242069Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3856802026-05-22T06:33:51Z
dc.title.none.fl_str_mv Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
title Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
spellingShingle Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
Domínguez-Martín, Helena
Proteotoxic stress
Autophagy
Microglia
Neurons
Phagocytosis
Proteasome
Proteostasis
title_short Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
title_full Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
title_fullStr Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
title_full_unstemmed Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
title_sort Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines
dc.creator.none.fl_str_mv Domínguez-Martín, Helena
Gavilán, Elena
Parrado, Celia
Burguillos, Miguel Ángel
Daza, Paula
Ruano, Diego
author Domínguez-Martín, Helena
author_facet Domínguez-Martín, Helena
Gavilán, Elena
Parrado, Celia
Burguillos, Miguel Ángel
Daza, Paula
Ruano, Diego
author_role author
author2 Gavilán, Elena
Parrado, Celia
Burguillos, Miguel Ángel
Daza, Paula
Ruano, Diego
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Junta de Andalucía
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
European Commission
Gavilán, Elena [0000-0002-8173-2638]
Burguillos, Miguel Ángel [0000-0002-3165-9997]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Proteotoxic stress
Autophagy
Microglia
Neurons
Phagocytosis
Proteasome
Proteostasis
topic Proteotoxic stress
Autophagy
Microglia
Neurons
Phagocytosis
Proteasome
Proteostasis
description Autophagy is a catabolic process involved in different cellular functions. However, the molecular pathways governing its potential roles in different cell types remain poorly understood. We investigated the role of autophagy in the context of proteotoxic stress in two central nervous system cell types: the microglia-like cell line BV2 and the neuronal-like cell line N2a. Proteotoxic stress, induced by proteasome inhibition, produced early apoptosis in BV2 cells, due in part to a predominant activation of the PERK-CHOP pathway. In contrast, N2a cells showcased greater resistance and robust induction of the IRE1α-sXbp1 arm of the UPR. We also demonstrated that proteotoxic stress activated autophagy in both cell lines but with different kinetics and cellular functions. In N2a cells, autophagy restored cellular proteostasis, while in BV2 cells, it participated in regulating phagocytosis. Finally, proteotoxic stress predominantly activated the mTORC2-AKT-FOXO1-β-catenin pathway in BV2 cells, while N2a cells preferentially induced the PDK1-AKT-FOXO3 axis. Collectively, our findings suggest that proteotoxic stress triggers cell-specific responses in microglia and neurons, with different physiological outcomes.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/385680
https://api.elsevier.com/content/abstract/scopus_id/85213341334
url http://hdl.handle.net/10261/385680
https://api.elsevier.com/content/abstract/scopus_id/85213341334
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136485OB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/cells13242069
https://doi.org/10.3390/cells13242069
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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