Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggr...

Descripción completa

Detalles Bibliográficos
Autores: Guerrero-Gómez, David, Mora-Lorca, José Antonio, Sáenz, Beatriz, Naranjo-Galindo, Francisco José, Muñoz-Lobato, Fernando, Parrado-Fernández, Cristina, Goikolea, Julen, Cedazo-Mínguez, Ángel, Link, Chris D., Neri, Christian, Sequedo, María Dolores, Vázquez-Manrique, Rafael P., Fernández-Suárez, Elena, Goder, Veit, Pané, Roser, Cabiscol, Elisa, Askjaer, Peter, Cabello, Juan, Miranda-Vizuete, Antonio
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/203270
Acceso en línea:http://hdl.handle.net/10261/203270
Access Level:acceso abierto
id ES_0ff2e3fd5c885e70f109ec8eaae48c68
oai_identifier_str oai:digital.csic.es:10261/203270
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
title Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
spellingShingle Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
Guerrero-Gómez, David
title_short Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
title_full Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
title_fullStr Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
title_full_unstemmed Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
title_sort Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
dc.creator.none.fl_str_mv Guerrero-Gómez, David
Mora-Lorca, José Antonio
Sáenz, Beatriz
Naranjo-Galindo, Francisco José
Muñoz-Lobato, Fernando
Parrado-Fernández, Cristina
Goikolea, Julen
Cedazo-Mínguez, Ángel
Link, Chris D.
Neri, Christian
Sequedo, María Dolores
Vázquez-Manrique, Rafael P.
Fernández-Suárez, Elena
Goder, Veit
Pané, Roser
Cabiscol, Elisa
Askjaer, Peter
Cabello, Juan
Miranda-Vizuete, Antonio
author Guerrero-Gómez, David
author_facet Guerrero-Gómez, David
Mora-Lorca, José Antonio
Sáenz, Beatriz
Naranjo-Galindo, Francisco José
Muñoz-Lobato, Fernando
Parrado-Fernández, Cristina
Goikolea, Julen
Cedazo-Mínguez, Ángel
Link, Chris D.
Neri, Christian
Sequedo, María Dolores
Vázquez-Manrique, Rafael P.
Fernández-Suárez, Elena
Goder, Veit
Pané, Roser
Cabiscol, Elisa
Askjaer, Peter
Cabello, Juan
Miranda-Vizuete, Antonio
author_role author
author2 Mora-Lorca, José Antonio
Sáenz, Beatriz
Naranjo-Galindo, Francisco José
Muñoz-Lobato, Fernando
Parrado-Fernández, Cristina
Goikolea, Julen
Cedazo-Mínguez, Ángel
Link, Chris D.
Neri, Christian
Sequedo, María Dolores
Vázquez-Manrique, Rafael P.
Fernández-Suárez, Elena
Goder, Veit
Pané, Roser
Cabiscol, Elisa
Askjaer, Peter
Cabello, Juan
Miranda-Vizuete, Antonio
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Knut and Alice Wallenberg Foundation
Swedish Research Council
Center for Innovative Medicine (Sweden)
Jonasson Centre for Medical Imaging (Sweden)
Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/203270
url http://hdl.handle.net/10261/203270
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-78265-P
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-79313-P
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/MDM-2016-0687
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-64408-P
https://doi.org/10.1038/s41418-018-0270-9
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
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
_version_ 1869403482960691200
spelling Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradationGuerrero-Gómez, DavidMora-Lorca, José AntonioSáenz, BeatrizNaranjo-Galindo, Francisco JoséMuñoz-Lobato, FernandoParrado-Fernández, CristinaGoikolea, JulenCedazo-Mínguez, ÁngelLink, Chris D.Neri, ChristianSequedo, María DoloresVázquez-Manrique, Rafael P.Fernández-Suárez, ElenaGoder, VeitPané, RoserCabiscol, ElisaAskjaer, PeterCabello, JuanMiranda-Vizuete, AntonioIn the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.Cristina Ayuso García and the Live Cell Imaging Facility, Karolinska Institutet, Sweden (supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Centre for Innovative Medicine and the Jonasson Centre at RIT, Sweden) are acknowledged for technical assistance. The Spanish Ministry of Economy and Competitiveness supported EF-S and VG (BFU2016–78265-P), PA (BFU2016–79313-P and MDM-2016–0687), and AM-V (BFU2015–64408-P). AM-V was also supported by the Instituto de Salud Carlos III (PI11/00072) and RPV-M (CPII16/00004, PI14/00949 and PI17/00011). All projects were cofinanced by the Fondo Social Europeo (FEDER). AM-V is a member of the GENIE and EU-ROS Cost Actions of the European Union and RPV-M is a Marie Curie Fellow (CIG322034, EU).Peer reviewedSpringer NatureKnut and Alice Wallenberg FoundationSwedish Research CouncilCenter for Innovative Medicine (Sweden)Jonasson Centre for Medical Imaging (Sweden)Ministerio de Economía y Competitividad (España)Instituto de Salud Carlos IIIEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/203270reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-78265-Pinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-79313-Pinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/MDM-2016-0687info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-64408-Phttps://doi.org/10.1038/s41418-018-0270-9Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2032702026-05-22T06:33:51Z
score 15,812455

Similares en LA Referencia