An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi

Autores
Sternlieb, Tamara; Schoijet, Alejandra Cecilia; Genta, Patricio D.; Vilchez Larrea, Salomé Catalina; Alonso, Guillermo Daniel
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Trypanosoma cruzi, the etiological agent of Chagas disease, has a digenetic life cycle. In itspassage from the insect vector to the mammalian host, and vice versa, it must be preparedto cope with abrupt changes in environmental conditions, such as carbon source, pH, temperatureand osmolarity, in order to survive. Sensing and signaling pathways that allow theparasite to adapt, have unique characteristics with respect to their hosts and other free-livingorganisms. Many of the canonical proteins involved in these transduction pathways havenot yet been found in the genomes of these parasites because they present divergenceseither at the functional, structural and/or protein sequence level. All of this makes thesepathways promising targets for therapeutic drugs. The AMP-activated protein kinase(AMPK) is a serine/threonine kinase activated by environmental stresses such as osmoticstress, hypoxia, ischaemia and exercise that results in reduction of ATP and increase ofAMP levels. Thus, AMPK is regarded as a fuel gauge, functioning both as a nutrient and anenergy sensor, to maintain energy homeostasis and, eventually, to protect cells from deathby nutrient starvation. In the present study we report the characterization of AMPK complexesfor the first time in T. cruzi and propose the function of TcAMPK as a novel regulatorof nutritional stress in epimastigote forms. We show that there is phosphotransferase activityspecific for SAMS peptide in epimastigotes extracts, which is inhibited by Compound C andis modulated by carbon source availability. In addition, TcAMPKα2 subunit has an unprecedentedfunctional substitution (Ser x Thr) at the activation loop and its overexpression in epimastigotesled to higher autophagic activity during prolonged nutritional stress. Moreover,the over-expression of the catalytic subunits resulted in antagonistic phenotypes associatedwith proliferation. Together, these results point to a role of TcAMPK in autophagy and nutrient sensing, key processes for the survival of trypanosomatids and for its life cycleprogression.
Fil: Sternlieb, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Schoijet, Alejandra Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Genta, Patricio D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Materia
Trypanosoma cruzi
AMPK
Phosphorylation
Autophagy
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:11336/138059

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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruziSternlieb, TamaraSchoijet, Alejandra CeciliaGenta, Patricio D.Vilchez Larrea, Salomé CatalinaAlonso, Guillermo DanielTrypanosoma cruziAMPKPhosphorylationAutophagyhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Trypanosoma cruzi, the etiological agent of Chagas disease, has a digenetic life cycle. In itspassage from the insect vector to the mammalian host, and vice versa, it must be preparedto cope with abrupt changes in environmental conditions, such as carbon source, pH, temperatureand osmolarity, in order to survive. Sensing and signaling pathways that allow theparasite to adapt, have unique characteristics with respect to their hosts and other free-livingorganisms. Many of the canonical proteins involved in these transduction pathways havenot yet been found in the genomes of these parasites because they present divergenceseither at the functional, structural and/or protein sequence level. All of this makes thesepathways promising targets for therapeutic drugs. The AMP-activated protein kinase(AMPK) is a serine/threonine kinase activated by environmental stresses such as osmoticstress, hypoxia, ischaemia and exercise that results in reduction of ATP and increase ofAMP levels. Thus, AMPK is regarded as a fuel gauge, functioning both as a nutrient and anenergy sensor, to maintain energy homeostasis and, eventually, to protect cells from deathby nutrient starvation. In the present study we report the characterization of AMPK complexesfor the first time in T. cruzi and propose the function of TcAMPK as a novel regulatorof nutritional stress in epimastigote forms. We show that there is phosphotransferase activityspecific for SAMS peptide in epimastigotes extracts, which is inhibited by Compound C andis modulated by carbon source availability. In addition, TcAMPKα2 subunit has an unprecedentedfunctional substitution (Ser x Thr) at the activation loop and its overexpression in epimastigotesled to higher autophagic activity during prolonged nutritional stress. Moreover,the over-expression of the catalytic subunits resulted in antagonistic phenotypes associatedwith proliferation. Together, these results point to a role of TcAMPK in autophagy and nutrient sensing, key processes for the survival of trypanosomatids and for its life cycleprogression.Fil: Sternlieb, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Schoijet, Alejandra Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Genta, Patricio D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaPublic Library of Science2021-05-24info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/138059Sternlieb, Tamara; Schoijet, Alejandra Cecilia; Genta, Patricio D.; Vilchez Larrea, Salomé Catalina; Alonso, Guillermo Daniel; An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi; Public Library of Science; Plos Neglected Tropical Diseases; 15; 5; 24-5-2021; 1-221935-2735CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://dx.plos.org/10.1371/journal.pntd.0009435info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0009435info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:33:00Zoai:ri.conicet.gov.ar:11336/138059instacron: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:34982025-09-29 09:33:00.803CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi
title An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi
spellingShingle An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi
Sternlieb, Tamara
Trypanosoma cruzi
AMPK
Phosphorylation
Autophagy
title_short An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi
title_full An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi
title_fullStr An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi
title_full_unstemmed An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi
title_sort An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi
dc.creator.none.fl_str_mv Sternlieb, Tamara
Schoijet, Alejandra Cecilia
Genta, Patricio D.
Vilchez Larrea, Salomé Catalina
Alonso, Guillermo Daniel
author Sternlieb, Tamara
author_facet Sternlieb, Tamara
Schoijet, Alejandra Cecilia
Genta, Patricio D.
Vilchez Larrea, Salomé Catalina
Alonso, Guillermo Daniel
author_role author
author2 Schoijet, Alejandra Cecilia
Genta, Patricio D.
Vilchez Larrea, Salomé Catalina
Alonso, Guillermo Daniel
author2_role author
author
author
author
dc.subject.none.fl_str_mv Trypanosoma cruzi
AMPK
Phosphorylation
Autophagy
topic Trypanosoma cruzi
AMPK
Phosphorylation
Autophagy
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Trypanosoma cruzi, the etiological agent of Chagas disease, has a digenetic life cycle. In itspassage from the insect vector to the mammalian host, and vice versa, it must be preparedto cope with abrupt changes in environmental conditions, such as carbon source, pH, temperatureand osmolarity, in order to survive. Sensing and signaling pathways that allow theparasite to adapt, have unique characteristics with respect to their hosts and other free-livingorganisms. Many of the canonical proteins involved in these transduction pathways havenot yet been found in the genomes of these parasites because they present divergenceseither at the functional, structural and/or protein sequence level. All of this makes thesepathways promising targets for therapeutic drugs. The AMP-activated protein kinase(AMPK) is a serine/threonine kinase activated by environmental stresses such as osmoticstress, hypoxia, ischaemia and exercise that results in reduction of ATP and increase ofAMP levels. Thus, AMPK is regarded as a fuel gauge, functioning both as a nutrient and anenergy sensor, to maintain energy homeostasis and, eventually, to protect cells from deathby nutrient starvation. In the present study we report the characterization of AMPK complexesfor the first time in T. cruzi and propose the function of TcAMPK as a novel regulatorof nutritional stress in epimastigote forms. We show that there is phosphotransferase activityspecific for SAMS peptide in epimastigotes extracts, which is inhibited by Compound C andis modulated by carbon source availability. In addition, TcAMPKα2 subunit has an unprecedentedfunctional substitution (Ser x Thr) at the activation loop and its overexpression in epimastigotesled to higher autophagic activity during prolonged nutritional stress. Moreover,the over-expression of the catalytic subunits resulted in antagonistic phenotypes associatedwith proliferation. Together, these results point to a role of TcAMPK in autophagy and nutrient sensing, key processes for the survival of trypanosomatids and for its life cycleprogression.
Fil: Sternlieb, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Schoijet, Alejandra Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Genta, Patricio D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
description Trypanosoma cruzi, the etiological agent of Chagas disease, has a digenetic life cycle. In itspassage from the insect vector to the mammalian host, and vice versa, it must be preparedto cope with abrupt changes in environmental conditions, such as carbon source, pH, temperatureand osmolarity, in order to survive. Sensing and signaling pathways that allow theparasite to adapt, have unique characteristics with respect to their hosts and other free-livingorganisms. Many of the canonical proteins involved in these transduction pathways havenot yet been found in the genomes of these parasites because they present divergenceseither at the functional, structural and/or protein sequence level. All of this makes thesepathways promising targets for therapeutic drugs. The AMP-activated protein kinase(AMPK) is a serine/threonine kinase activated by environmental stresses such as osmoticstress, hypoxia, ischaemia and exercise that results in reduction of ATP and increase ofAMP levels. Thus, AMPK is regarded as a fuel gauge, functioning both as a nutrient and anenergy sensor, to maintain energy homeostasis and, eventually, to protect cells from deathby nutrient starvation. In the present study we report the characterization of AMPK complexesfor the first time in T. cruzi and propose the function of TcAMPK as a novel regulatorof nutritional stress in epimastigote forms. We show that there is phosphotransferase activityspecific for SAMS peptide in epimastigotes extracts, which is inhibited by Compound C andis modulated by carbon source availability. In addition, TcAMPKα2 subunit has an unprecedentedfunctional substitution (Ser x Thr) at the activation loop and its overexpression in epimastigotesled to higher autophagic activity during prolonged nutritional stress. Moreover,the over-expression of the catalytic subunits resulted in antagonistic phenotypes associatedwith proliferation. Together, these results point to a role of TcAMPK in autophagy and nutrient sensing, key processes for the survival of trypanosomatids and for its life cycleprogression.
publishDate 2021
dc.date.none.fl_str_mv 2021-05-24
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/138059
Sternlieb, Tamara; Schoijet, Alejandra Cecilia; Genta, Patricio D.; Vilchez Larrea, Salomé Catalina; Alonso, Guillermo Daniel; An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi; Public Library of Science; Plos Neglected Tropical Diseases; 15; 5; 24-5-2021; 1-22
1935-2735
CONICET Digital
CONICET
url http://hdl.handle.net/11336/138059
identifier_str_mv Sternlieb, Tamara; Schoijet, Alejandra Cecilia; Genta, Patricio D.; Vilchez Larrea, Salomé Catalina; Alonso, Guillermo Daniel; An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi; Public Library of Science; Plos Neglected Tropical Diseases; 15; 5; 24-5-2021; 1-22
1935-2735
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://dx.plos.org/10.1371/journal.pntd.0009435
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0009435
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
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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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