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

first_pagesettingsOrder Article Reprints Open AccessArticle Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines by Helena Domínguez-Martín 1,2,†,Elena Gavilán 1,2,†ORCID,Celia Parrado 1,Miguel A. Burguillos 1,2ORCID,Paula D...

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Authors: Domínguez Martín, Helena, Gavilán Dorronzoro, Elena, Parrado, Celia, Burguillos García, Miguel Ángel, Daza Navarro, María Paula, Ruano Caballero, Diego
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Universidad de Sevilla (US)
Repository:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/168710
Online Access:https://hdl.handle.net/11441/168710
https://doi.org/10.3390/cells13242069
Access Level:Open access
Keyword:proteotoxic stress
autophagy
proteasome
microglia
neurons
phagocytosis
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 Dorronzoro, ElenaParrado, CeliaBurguillos García, Miguel ÁngelDaza Navarro, María PaulaRuano Caballero, Diegoproteotoxic stressautophagyproteasomemicroglianeuronsphagocytosisproteostasisfirst_pagesettingsOrder Article Reprints Open AccessArticle Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines by Helena Domínguez-Martín 1,2,†,Elena Gavilán 1,2,†ORCID,Celia Parrado 1,Miguel A. Burguillos 1,2ORCID,Paula Daza 3 andDiego Ruano 1,2,* 1 Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla (US), 41012 Sevilla, Spain 2 Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla (US), 41013 Sevilla, Spain 3 Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla (US), 41012 Sevilla, Spain * Author to whom correspondence should be addressed. † These authors contributed equally to this work and share first authorship. Cells 2024, 13(24), 2069; https://doi.org/10.3390/cells13242069 Submission received: 4 November 2024 / Revised: 10 December 2024 / Accepted: 13 December 2024 / Published: 15 December 2024 (This article belongs to the Special Issue Understanding the Interplay Between Autophagy and Neurodegeneration) Downloadkeyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract 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.Junta de Andalucía CTS257-Envejecimiento y NeurodegeneraciónMICIU/AEI/10.13039/501100011033 y Unión Europea NextGenerationEU/PRTR - CNS2022-135867MICIU/AEI/10.13039/501100011033 y FEDER, UE - PID2022-136485OB-I00MDPIBiología CelularBioquímica y Biología MolecularCTS257: Envejecimiento y NeurodegeneraciónJunta de AndalucíaMinisterio de Ciencia, Innovación y Universidades (MICIU). EspañaAgencia Estatal de Investigación. EspañaUnión Europea NextGenerationEuropean Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/168710https://doi.org/10.3390/cells13242069reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésCells, 13 (24), 2069.CTS257CNS2022-135867PID2022-136485OB-I00https://doi.org/10.3390/cells13242069info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1687102026-06-17T12:51:07Z
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
proteasome
microglia
neurons
phagocytosis
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 Dorronzoro, Elena
Parrado, Celia
Burguillos García, Miguel Ángel
Daza Navarro, María Paula
Ruano Caballero, Diego
author Domínguez Martín, Helena
author_facet Domínguez Martín, Helena
Gavilán Dorronzoro, Elena
Parrado, Celia
Burguillos García, Miguel Ángel
Daza Navarro, María Paula
Ruano Caballero, Diego
author_role author
author2 Gavilán Dorronzoro, Elena
Parrado, Celia
Burguillos García, Miguel Ángel
Daza Navarro, María Paula
Ruano Caballero, Diego
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Biología Celular
Bioquímica y Biología Molecular
CTS257: Envejecimiento y Neurodegeneración
Junta de Andalucía
Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Agencia Estatal de Investigación. España
Unión Europea NextGeneration
European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
dc.subject.none.fl_str_mv proteotoxic stress
autophagy
proteasome
microglia
neurons
phagocytosis
proteostasis
topic proteotoxic stress
autophagy
proteasome
microglia
neurons
phagocytosis
proteostasis
description first_pagesettingsOrder Article Reprints Open AccessArticle Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines by Helena Domínguez-Martín 1,2,†,Elena Gavilán 1,2,†ORCID,Celia Parrado 1,Miguel A. Burguillos 1,2ORCID,Paula Daza 3 andDiego Ruano 1,2,* 1 Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla (US), 41012 Sevilla, Spain 2 Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla (US), 41013 Sevilla, Spain 3 Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla (US), 41012 Sevilla, Spain * Author to whom correspondence should be addressed. † These authors contributed equally to this work and share first authorship. Cells 2024, 13(24), 2069; https://doi.org/10.3390/cells13242069 Submission received: 4 November 2024 / Revised: 10 December 2024 / Accepted: 13 December 2024 / Published: 15 December 2024 (This article belongs to the Special Issue Understanding the Interplay Between Autophagy and Neurodegeneration) Downloadkeyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract 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
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/168710
https://doi.org/10.3390/cells13242069
url https://hdl.handle.net/11441/168710
https://doi.org/10.3390/cells13242069
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cells, 13 (24), 2069.
CTS257
CNS2022-135867
PID2022-136485OB-I00
https://doi.org/10.3390/cells13242069
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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