Deciphering the Role of TFEB in Echinococcus granulosus larval stage

Autores
Franco, Micaela; Lausero, Luciano Nicolás; Nieto, Sabrina; Pastrello, Ivana Yael; Loos, Julia Alexandra; Cumino, Andrea Carina
Año de publicación
2024
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Autophagy and lysosomal activity are adaptation mechanisms used by the Echinococcus granulosus in response to different metabolic contexts or stressors. Cestode lack of excretory and digestive systems, therefore they required high lysosomal activity to cope with their metabolism. In this line evidence, previously we demonstrated the occurrence of a single functional ortholog of the MiT/TFE family transcription factors in Echinococcus larval stages, Eg-TFEB, a bHLH-ZIP-type protein with a modular sequence involved in lysosomal biogénesis, autophagy and exocytosis. Based on Eg-TFEB conserved structure and its high level of endogenous expression, in situ immunodetection resulted appropriate as a method to verify its subcellular localization in the parasite. Eg-TFEB conserve a Ser199 residue phosphorylatable by TOR (equivalent to Ser211 of Homo sapiens TFEB), through which can to inhibit its activity by promoting its retention in the cytoplasm. During starvation and mTOR inactivation, TFEB is dephosphorylated and translocated to the nucleus, where it can promote the expression of its target genes. Rapamycin, hydroxychloroquine and metformin act as Eg-TFEB activators, promoting its nuclear localization. In this scenario, Eg-TFEB binds to palindromic CLEAR motifs (GTCACGTGAC) present in promoters of target genes, activating transcriptional expression and favoring processes such as autophagy (atg5, atg7, atg8.2 and atg12), lysosomal (lal-1, lal-2, atp6V1 and clcn7), metabolic activity (glut-1 and glut1-4), and even its own transcription. Contrarily to expectations, calcineurin is not involved in the activation of Eg-TFEB, due to its subcellular localization unchanged in presence of cyclosporine A. Finally, this work describes the in vitro dose-dependent anti-echinococcal effects exerted by eltrombopag (FDA-approved drug) on metacestodes, drug that specifically binds to helix-loop-helix region disrupting the TFEB-DNA interaction, highlighting TFEB as a druggable target for autophagy, a promising strategy for anti-cestodal therapy.
Fil: Franco, Micaela. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Lausero, Luciano Nicolás. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Nieto, Sabrina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Pastrello, Ivana Yael. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina
Fil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
XXVII Congreso de la Federación Latinoamericana de Parasitología (FLAP 2024)
Buenos Aires
Argentina
Sociedad Argentina de Protozoología
Materia
TFEB
Echinococcus
TORC1 regulation
eltrombopag
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/275311
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/275311
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Deciphering the Role of TFEB in Echinococcus granulosus larval stageFranco, MicaelaLausero, Luciano NicolásNieto, SabrinaPastrello, Ivana YaelLoos, Julia AlexandraCumino, Andrea CarinaTFEBEchinococcusTORC1 regulationeltrombopaghttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Autophagy and lysosomal activity are adaptation mechanisms used by the Echinococcus granulosus in response to different metabolic contexts or stressors. Cestode lack of excretory and digestive systems, therefore they required high lysosomal activity to cope with their metabolism. In this line evidence, previously we demonstrated the occurrence of a single functional ortholog of the MiT/TFE family transcription factors in Echinococcus larval stages, Eg-TFEB, a bHLH-ZIP-type protein with a modular sequence involved in lysosomal biogénesis, autophagy and exocytosis. Based on Eg-TFEB conserved structure and its high level of endogenous expression, in situ immunodetection resulted appropriate as a method to verify its subcellular localization in the parasite. Eg-TFEB conserve a Ser199 residue phosphorylatable by TOR (equivalent to Ser211 of Homo sapiens TFEB), through which can to inhibit its activity by promoting its retention in the cytoplasm. During starvation and mTOR inactivation, TFEB is dephosphorylated and translocated to the nucleus, where it can promote the expression of its target genes. Rapamycin, hydroxychloroquine and metformin act as Eg-TFEB activators, promoting its nuclear localization. In this scenario, Eg-TFEB binds to palindromic CLEAR motifs (GTCACGTGAC) present in promoters of target genes, activating transcriptional expression and favoring processes such as autophagy (atg5, atg7, atg8.2 and atg12), lysosomal (lal-1, lal-2, atp6V1 and clcn7), metabolic activity (glut-1 and glut1-4), and even its own transcription. Contrarily to expectations, calcineurin is not involved in the activation of Eg-TFEB, due to its subcellular localization unchanged in presence of cyclosporine A. Finally, this work describes the in vitro dose-dependent anti-echinococcal effects exerted by eltrombopag (FDA-approved drug) on metacestodes, drug that specifically binds to helix-loop-helix region disrupting the TFEB-DNA interaction, highlighting TFEB as a druggable target for autophagy, a promising strategy for anti-cestodal therapy.Fil: Franco, Micaela. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; ArgentinaFil: Lausero, Luciano Nicolás. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; ArgentinaFil: Nieto, Sabrina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; ArgentinaFil: Pastrello, Ivana Yael. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; ArgentinaFil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; ArgentinaXXVII Congreso de la Federación Latinoamericana de Parasitología (FLAP 2024)Buenos AiresArgentinaSociedad Argentina de ProtozoologíaSociedad Argentina de Protozoología2024info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/275311Deciphering the Role of TFEB in Echinococcus granulosus larval stage; XXVII Congreso de la Federación Latinoamericana de Parasitología (FLAP 2024); Buenos Aires; Argentina; 2024; 99-1002953-5751CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://protozoologia.org.ar/revista-parasitus/Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-23T13:22:13Zoai:ri.conicet.gov.ar:11336/275311instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-12-23 13:22:14.135CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Deciphering the Role of TFEB in Echinococcus granulosus larval stage
title Deciphering the Role of TFEB in Echinococcus granulosus larval stage
spellingShingle Deciphering the Role of TFEB in Echinococcus granulosus larval stage
Franco, Micaela
TFEB
Echinococcus
TORC1 regulation
eltrombopag
title_short Deciphering the Role of TFEB in Echinococcus granulosus larval stage
title_full Deciphering the Role of TFEB in Echinococcus granulosus larval stage
title_fullStr Deciphering the Role of TFEB in Echinococcus granulosus larval stage
title_full_unstemmed Deciphering the Role of TFEB in Echinococcus granulosus larval stage
title_sort Deciphering the Role of TFEB in Echinococcus granulosus larval stage
dc.creator.none.fl_str_mv Franco, Micaela
Lausero, Luciano Nicolás
Nieto, Sabrina
Pastrello, Ivana Yael
Loos, Julia Alexandra
Cumino, Andrea Carina
author Franco, Micaela
author_facet Franco, Micaela
Lausero, Luciano Nicolás
Nieto, Sabrina
Pastrello, Ivana Yael
Loos, Julia Alexandra
Cumino, Andrea Carina
author_role author
author2 Lausero, Luciano Nicolás
Nieto, Sabrina
Pastrello, Ivana Yael
Loos, Julia Alexandra
Cumino, Andrea Carina
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv TFEB
Echinococcus
TORC1 regulation
eltrombopag
topic TFEB
Echinococcus
TORC1 regulation
eltrombopag
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Autophagy and lysosomal activity are adaptation mechanisms used by the Echinococcus granulosus in response to different metabolic contexts or stressors. Cestode lack of excretory and digestive systems, therefore they required high lysosomal activity to cope with their metabolism. In this line evidence, previously we demonstrated the occurrence of a single functional ortholog of the MiT/TFE family transcription factors in Echinococcus larval stages, Eg-TFEB, a bHLH-ZIP-type protein with a modular sequence involved in lysosomal biogénesis, autophagy and exocytosis. Based on Eg-TFEB conserved structure and its high level of endogenous expression, in situ immunodetection resulted appropriate as a method to verify its subcellular localization in the parasite. Eg-TFEB conserve a Ser199 residue phosphorylatable by TOR (equivalent to Ser211 of Homo sapiens TFEB), through which can to inhibit its activity by promoting its retention in the cytoplasm. During starvation and mTOR inactivation, TFEB is dephosphorylated and translocated to the nucleus, where it can promote the expression of its target genes. Rapamycin, hydroxychloroquine and metformin act as Eg-TFEB activators, promoting its nuclear localization. In this scenario, Eg-TFEB binds to palindromic CLEAR motifs (GTCACGTGAC) present in promoters of target genes, activating transcriptional expression and favoring processes such as autophagy (atg5, atg7, atg8.2 and atg12), lysosomal (lal-1, lal-2, atp6V1 and clcn7), metabolic activity (glut-1 and glut1-4), and even its own transcription. Contrarily to expectations, calcineurin is not involved in the activation of Eg-TFEB, due to its subcellular localization unchanged in presence of cyclosporine A. Finally, this work describes the in vitro dose-dependent anti-echinococcal effects exerted by eltrombopag (FDA-approved drug) on metacestodes, drug that specifically binds to helix-loop-helix region disrupting the TFEB-DNA interaction, highlighting TFEB as a druggable target for autophagy, a promising strategy for anti-cestodal therapy.
Fil: Franco, Micaela. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Lausero, Luciano Nicolás. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Nieto, Sabrina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Pastrello, Ivana Yael. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina
Fil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
XXVII Congreso de la Federación Latinoamericana de Parasitología (FLAP 2024)
Buenos Aires
Argentina
Sociedad Argentina de Protozoología
description Autophagy and lysosomal activity are adaptation mechanisms used by the Echinococcus granulosus in response to different metabolic contexts or stressors. Cestode lack of excretory and digestive systems, therefore they required high lysosomal activity to cope with their metabolism. In this line evidence, previously we demonstrated the occurrence of a single functional ortholog of the MiT/TFE family transcription factors in Echinococcus larval stages, Eg-TFEB, a bHLH-ZIP-type protein with a modular sequence involved in lysosomal biogénesis, autophagy and exocytosis. Based on Eg-TFEB conserved structure and its high level of endogenous expression, in situ immunodetection resulted appropriate as a method to verify its subcellular localization in the parasite. Eg-TFEB conserve a Ser199 residue phosphorylatable by TOR (equivalent to Ser211 of Homo sapiens TFEB), through which can to inhibit its activity by promoting its retention in the cytoplasm. During starvation and mTOR inactivation, TFEB is dephosphorylated and translocated to the nucleus, where it can promote the expression of its target genes. Rapamycin, hydroxychloroquine and metformin act as Eg-TFEB activators, promoting its nuclear localization. In this scenario, Eg-TFEB binds to palindromic CLEAR motifs (GTCACGTGAC) present in promoters of target genes, activating transcriptional expression and favoring processes such as autophagy (atg5, atg7, atg8.2 and atg12), lysosomal (lal-1, lal-2, atp6V1 and clcn7), metabolic activity (glut-1 and glut1-4), and even its own transcription. Contrarily to expectations, calcineurin is not involved in the activation of Eg-TFEB, due to its subcellular localization unchanged in presence of cyclosporine A. Finally, this work describes the in vitro dose-dependent anti-echinococcal effects exerted by eltrombopag (FDA-approved drug) on metacestodes, drug that specifically binds to helix-loop-helix region disrupting the TFEB-DNA interaction, highlighting TFEB as a druggable target for autophagy, a promising strategy for anti-cestodal therapy.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/275311
Deciphering the Role of TFEB in Echinococcus granulosus larval stage; XXVII Congreso de la Federación Latinoamericana de Parasitología (FLAP 2024); Buenos Aires; Argentina; 2024; 99-100
2953-5751
CONICET Digital
CONICET
url http://hdl.handle.net/11336/275311
identifier_str_mv Deciphering the Role of TFEB in Echinococcus granulosus larval stage; XXVII Congreso de la Federación Latinoamericana de Parasitología (FLAP 2024); Buenos Aires; Argentina; 2024; 99-100
2953-5751
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://protozoologia.org.ar/revista-parasitus/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Protozoología
publisher.none.fl_str_mv Sociedad Argentina de Protozoología
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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