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...

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Autores: Guerrero-Gómez, David, Mora-Lorca, José Antonio, Sáenz-Narciso, Beatriz, Naranjo-Galindo, Francisco José, Muñoz-Lobato, Fernando, Parrado-Fernández, Cristina, Goikolea, Julen, Cedazo-Minguez, Ángel, Link, Christopher D., Neri, Christian, Sequedo, María Dolores, Vázquez-Manrique, Rafael P., Fernández-Suárez, Elena, Goder, Veit, Pane Domenec, Roser, Cabiscol Català, Elisa, Askjaer, Peter, Cabello, Juan, Miranda-Vizuete, Antonio
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/72704
Acceso en línea:https://doi.org/10.1038/s41418-018-0270-9
http://hdl.handle.net/10459.1/72704
Access Level:acceso abierto
Palabra clave:Autophagy
Caenorhabditis elegans
Cell blebbing
Diethyl maleate
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repository_id_str
spelling Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradationGuerrero-Gómez, DavidMora-Lorca, José AntonioSáenz-Narciso, BeatrizNaranjo-Galindo, Francisco JoséMuñoz-Lobato, FernandoParrado-Fernández, CristinaGoikolea, JulenCedazo-Minguez, ÁngelLink, Christopher D.Neri, ChristianSequedo, María DoloresVázquez-Manrique, Rafael P.Fernández-Suárez, ElenaGoder, VeitPane Domenec, RoserCabiscol Català, ElisaAskjaer, PeterCabello, JuanMiranda-Vizuete, AntonioAutophagyCaenorhabditis elegansCell blebbingDiethyl maleateIn 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.. 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).Springer Nature202220222019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionhttps://doi.org/10.1038/s41418-018-0270-9http://hdl.handle.net/10459.1/72704http://hdl.handle.net/10459.1/72704reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/grantAgreement/MINECO//BFU2016-78265-Pinfo:eu-repo/grantAgreement/MINECO//BFU2016-79313-Pinfo:eu-repo/grantAgreement/MINECO//BFU2015-64408-PVersió postprint del document publicat a https://doi.org/10.1038/s41418-018-0270-9Cell Death and Differentiation, 2009, vol. 26, núm. 9, p. 1545-1565(c) ADMC Associazione Differenziamento e Morte Cellulare, 2019info:eu-repo/semantics/openAccessoai:recercat.cat:10459.1/727042026-05-29T05:05:01Z
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
Autophagy
Caenorhabditis elegans
Cell blebbing
Diethyl maleate
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-Narciso, Beatriz
Naranjo-Galindo, Francisco José
Muñoz-Lobato, Fernando
Parrado-Fernández, Cristina
Goikolea, Julen
Cedazo-Minguez, Ángel
Link, Christopher D.
Neri, Christian
Sequedo, María Dolores
Vázquez-Manrique, Rafael P.
Fernández-Suárez, Elena
Goder, Veit
Pane Domenec, Roser
Cabiscol Català, Elisa
Askjaer, Peter
Cabello, Juan
Miranda-Vizuete, Antonio
author Guerrero-Gómez, David
author_facet Guerrero-Gómez, David
Mora-Lorca, José Antonio
Sáenz-Narciso, Beatriz
Naranjo-Galindo, Francisco José
Muñoz-Lobato, Fernando
Parrado-Fernández, Cristina
Goikolea, Julen
Cedazo-Minguez, Ángel
Link, Christopher D.
Neri, Christian
Sequedo, María Dolores
Vázquez-Manrique, Rafael P.
Fernández-Suárez, Elena
Goder, Veit
Pane Domenec, Roser
Cabiscol Català, Elisa
Askjaer, Peter
Cabello, Juan
Miranda-Vizuete, Antonio
author_role author
author2 Mora-Lorca, José Antonio
Sáenz-Narciso, Beatriz
Naranjo-Galindo, Francisco José
Muñoz-Lobato, Fernando
Parrado-Fernández, Cristina
Goikolea, Julen
Cedazo-Minguez, Ángel
Link, Christopher D.
Neri, Christian
Sequedo, María Dolores
Vázquez-Manrique, Rafael P.
Fernández-Suárez, Elena
Goder, Veit
Pane Domenec, Roser
Cabiscol Català, 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.subject.none.fl_str_mv Autophagy
Caenorhabditis elegans
Cell blebbing
Diethyl maleate
topic Autophagy
Caenorhabditis elegans
Cell blebbing
Diethyl maleate
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
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1038/s41418-018-0270-9
http://hdl.handle.net/10459.1/72704
http://hdl.handle.net/10459.1/72704
url https://doi.org/10.1038/s41418-018-0270-9
http://hdl.handle.net/10459.1/72704
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MINECO//BFU2016-78265-P
info:eu-repo/grantAgreement/MINECO//BFU2016-79313-P
info:eu-repo/grantAgreement/MINECO//BFU2015-64408-P
Versió postprint del document publicat a https://doi.org/10.1038/s41418-018-0270-9
Cell Death and Differentiation, 2009, vol. 26, núm. 9, p. 1545-1565
dc.rights.none.fl_str_mv (c) ADMC Associazione Differenziamento e Morte Cellulare, 2019
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) ADMC Associazione Differenziamento e Morte Cellulare, 2019
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:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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