The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI

Fluorizoline is a synthetic molecule that induces apoptosis, by selectively targeting prohibitins (PHBs), through induction of the BH3-only protein NOXA. This induction is transcriptionally regulated by the integrated stress response (ISR)-related transcription factors ATF3 and ATF4. Here, we evalua...

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Autores: Sánchez Vera, Ismael, Núñez Vázquez, Sonia, Saura Esteller, José, Cosialls Castel, Ana Mª, Heib, Judith, Nadal Rodríguez, Pau, Ghashghaei, Ouldouz, Lavilla Grífols, Rodolfo, Pons i Irazazábal, Gabriel, Gil i Santano, Joan, Iglesias i Serret, Daniel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
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:2445/200924
Acceso en línea:https://hdl.handle.net/2445/200924
Access Level:acceso abierto
Palabra clave:Apoptosi
Reticle endoplasmàtic
Apoptosis
Endoplasmic reticulum
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spelling The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRISánchez Vera, IsmaelNúñez Vázquez, SoniaSaura Esteller, JoséCosialls Castel, Ana MªHeib, JudithNadal Rodríguez, PauGhashghaei, OuldouzLavilla Grífols, RodolfoPons i Irazazábal, GabrielGil i Santano, JoanIglesias i Serret, DanielApoptosiReticle endoplasmàticApoptosisEndoplasmic reticulumFluorizoline is a synthetic molecule that induces apoptosis, by selectively targeting prohibitins (PHBs), through induction of the BH3-only protein NOXA. This induction is transcriptionally regulated by the integrated stress response (ISR)-related transcription factors ATF3 and ATF4. Here, we evaluate the role of the four eIF2a kinases, to decipher which is responsible for the mechanism of ISR activation triggered by fluorizoline in HeLa and HAP1 cells. First, we demonstrated the involvement of the eIF2a kinases using ISR inhibitor (ISRIB) and by simultaneous downregulation of all four eIF2a kinases, as both approaches were able to increase cell resistance to fluorizoline-induced apoptosis. Furthermore, we confirmed that fluorizoline treatment results in endoplasmic reticulum (ER) stress, as evidenced by PERK activation. Despite PERK activation, this kinase was not directly involved in the ISR activation by fluorizoline. In this regard, we found that the eIF2a kinases are capable of compensating for each other's loss of function. Importantly, we demonstrated that the mitochondrial-stress-related eIF2a kinase HRI mediates ISR activation after fluorizoline treatment.MDPI AG2023202320232023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion17 p.application/pdfhttps://hdl.handle.net/2445/200924Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3390/ijms24098064International Journal of Molecular Sciences, 2023, vol. 24, num. 9https://doi.org/10.3390/ijms24098064cc by (c) Sánchez Vera, Ismael et al., 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2009242026-05-29T05:05:01Z
dc.title.none.fl_str_mv The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI
title The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI
spellingShingle The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI
Sánchez Vera, Ismael
Apoptosi
Reticle endoplasmàtic
Apoptosis
Endoplasmic reticulum
title_short The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI
title_full The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI
title_fullStr The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI
title_full_unstemmed The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI
title_sort The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI
dc.creator.none.fl_str_mv Sánchez Vera, Ismael
Núñez Vázquez, Sonia
Saura Esteller, José
Cosialls Castel, Ana Mª
Heib, Judith
Nadal Rodríguez, Pau
Ghashghaei, Ouldouz
Lavilla Grífols, Rodolfo
Pons i Irazazábal, Gabriel
Gil i Santano, Joan
Iglesias i Serret, Daniel
author Sánchez Vera, Ismael
author_facet Sánchez Vera, Ismael
Núñez Vázquez, Sonia
Saura Esteller, José
Cosialls Castel, Ana Mª
Heib, Judith
Nadal Rodríguez, Pau
Ghashghaei, Ouldouz
Lavilla Grífols, Rodolfo
Pons i Irazazábal, Gabriel
Gil i Santano, Joan
Iglesias i Serret, Daniel
author_role author
author2 Núñez Vázquez, Sonia
Saura Esteller, José
Cosialls Castel, Ana Mª
Heib, Judith
Nadal Rodríguez, Pau
Ghashghaei, Ouldouz
Lavilla Grífols, Rodolfo
Pons i Irazazábal, Gabriel
Gil i Santano, Joan
Iglesias i Serret, Daniel
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Apoptosi
Reticle endoplasmàtic
Apoptosis
Endoplasmic reticulum
topic Apoptosi
Reticle endoplasmàtic
Apoptosis
Endoplasmic reticulum
description Fluorizoline is a synthetic molecule that induces apoptosis, by selectively targeting prohibitins (PHBs), through induction of the BH3-only protein NOXA. This induction is transcriptionally regulated by the integrated stress response (ISR)-related transcription factors ATF3 and ATF4. Here, we evaluate the role of the four eIF2a kinases, to decipher which is responsible for the mechanism of ISR activation triggered by fluorizoline in HeLa and HAP1 cells. First, we demonstrated the involvement of the eIF2a kinases using ISR inhibitor (ISRIB) and by simultaneous downregulation of all four eIF2a kinases, as both approaches were able to increase cell resistance to fluorizoline-induced apoptosis. Furthermore, we confirmed that fluorizoline treatment results in endoplasmic reticulum (ER) stress, as evidenced by PERK activation. Despite PERK activation, this kinase was not directly involved in the ISR activation by fluorizoline. In this regard, we found that the eIF2a kinases are capable of compensating for each other's loss of function. Importantly, we demonstrated that the mitochondrial-stress-related eIF2a kinase HRI mediates ISR activation after fluorizoline treatment.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
2023
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/2445/200924
url https://hdl.handle.net/2445/200924
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/ijms24098064
International Journal of Molecular Sciences, 2023, vol. 24, num. 9
https://doi.org/10.3390/ijms24098064
dc.rights.none.fl_str_mv cc by (c) Sánchez Vera, Ismael et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Sánchez Vera, Ismael et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 17 p.
application/pdf
dc.publisher.none.fl_str_mv MDPI AG
publisher.none.fl_str_mv MDPI AG
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
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
_version_ 1869406454239199232
score 15,81155

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