V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy

In addition to being a master regulator of cell cycle progression, E2F1 regulates other associated biological processes, including growth and malignancy. Here, we uncover a regulatory network linking E2F1 to lysosomal trafficking and mTORC1 signaling that involves v-ATPase regulation. By immunofluor...

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Autores: Meo Evoli, Nathalie, Almacellas i Canals, Eugènia, Massucci, Francesco Alessandro, Gentilella, Antonio, Ambrosio Viale, Santiago, Kozma, Sara C., Thomas, George, Tauler Girona, Albert
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/178752
Acceso en línea:https://hdl.handle.net/2445/178752
Access Level:acceso abierto
Palabra clave:Factors de transcripció
Proteïnes quinases
Protons
Transcription factors
Protein kinases
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spelling V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagyMeo Evoli, NathalieAlmacellas i Canals, EugèniaMassucci, Francesco AlessandroGentilella, AntonioAmbrosio Viale, SantiagoKozma, Sara C.Thomas, GeorgeTauler Girona, AlbertFactors de transcripcióProteïnes quinasesProtonsTranscription factorsProtein kinasesProtonsIn addition to being a master regulator of cell cycle progression, E2F1 regulates other associated biological processes, including growth and malignancy. Here, we uncover a regulatory network linking E2F1 to lysosomal trafficking and mTORC1 signaling that involves v-ATPase regulation. By immunofluorescence and time-lapse microscopy we found that E2F1 induces the movement of lysosomes to the cell periphery, and that this process is essential for E2F1-induced mTORC1 activation and repression of autophagy. Gain- and loss-of-function experiments reveal that E2F1 regulates v-ATPase activity and inhibition of v-ATPase activity repressed E2F1-induced lysosomal trafficking and mTORC1 activation. Immunoprecipitation experiments demonstrate that E2F1 induces the recruitment of v-ATPase to lysosomal RagB GTPase, suggesting that E2F1 regulates v-ATPase activity by enhancing the association of V0 and V1 v-ATPase complex. Analysis of v-ATPase subunit expression identified B subunit of V0 complex, ATP6V0B, as a transcriptional target of E2F1. Importantly, ATP6V0B ectopic-expression increased v-ATPase and mTORC1 activity, consistent with ATP6V0B being responsible for mediating the effects of E2F1 on both responses. Our findings on lysosomal trafficking, mTORC1 activation and autophagy suppression suggest that pharmacological intervention at the level of v-ATPase may be an efficacious avenue for the treatment of metastatic processes in tumors overexpressing E2F1.Impact Journals2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/178752Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.18632/oncotarget.4812Oncotarget, 2015, vol. 6, num. 29, p. 28057-28070https://doi.org/10.18632/oncotarget.4812cc-by (c) Meo Evoli, Nathalie et al., 2015https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1787522026-05-27T06:46:51Z
dc.title.none.fl_str_mv V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
title V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
spellingShingle V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
Meo Evoli, Nathalie
Factors de transcripció
Proteïnes quinases
Protons
Transcription factors
Protein kinases
Protons
title_short V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
title_full V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
title_fullStr V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
title_full_unstemmed V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
title_sort V-ATPase, a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
dc.creator.none.fl_str_mv Meo Evoli, Nathalie
Almacellas i Canals, Eugènia
Massucci, Francesco Alessandro
Gentilella, Antonio
Ambrosio Viale, Santiago
Kozma, Sara C.
Thomas, George
Tauler Girona, Albert
author Meo Evoli, Nathalie
author_facet Meo Evoli, Nathalie
Almacellas i Canals, Eugènia
Massucci, Francesco Alessandro
Gentilella, Antonio
Ambrosio Viale, Santiago
Kozma, Sara C.
Thomas, George
Tauler Girona, Albert
author_role author
author2 Almacellas i Canals, Eugènia
Massucci, Francesco Alessandro
Gentilella, Antonio
Ambrosio Viale, Santiago
Kozma, Sara C.
Thomas, George
Tauler Girona, Albert
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Factors de transcripció
Proteïnes quinases
Protons
Transcription factors
Protein kinases
Protons
topic Factors de transcripció
Proteïnes quinases
Protons
Transcription factors
Protein kinases
Protons
description In addition to being a master regulator of cell cycle progression, E2F1 regulates other associated biological processes, including growth and malignancy. Here, we uncover a regulatory network linking E2F1 to lysosomal trafficking and mTORC1 signaling that involves v-ATPase regulation. By immunofluorescence and time-lapse microscopy we found that E2F1 induces the movement of lysosomes to the cell periphery, and that this process is essential for E2F1-induced mTORC1 activation and repression of autophagy. Gain- and loss-of-function experiments reveal that E2F1 regulates v-ATPase activity and inhibition of v-ATPase activity repressed E2F1-induced lysosomal trafficking and mTORC1 activation. Immunoprecipitation experiments demonstrate that E2F1 induces the recruitment of v-ATPase to lysosomal RagB GTPase, suggesting that E2F1 regulates v-ATPase activity by enhancing the association of V0 and V1 v-ATPase complex. Analysis of v-ATPase subunit expression identified B subunit of V0 complex, ATP6V0B, as a transcriptional target of E2F1. Importantly, ATP6V0B ectopic-expression increased v-ATPase and mTORC1 activity, consistent with ATP6V0B being responsible for mediating the effects of E2F1 on both responses. Our findings on lysosomal trafficking, mTORC1 activation and autophagy suppression suggest that pharmacological intervention at the level of v-ATPase may be an efficacious avenue for the treatment of metastatic processes in tumors overexpressing E2F1.
publishDate 2015
dc.date.none.fl_str_mv 2015
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/2445/178752
url https://hdl.handle.net/2445/178752
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/10.18632/oncotarget.4812
Oncotarget, 2015, vol. 6, num. 29, p. 28057-28070
https://doi.org/10.18632/oncotarget.4812
dc.rights.none.fl_str_mv cc-by (c) Meo Evoli, Nathalie et al., 2015
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Meo Evoli, Nathalie et al., 2015
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869418971850080256
score 15,300719

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