An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone

Autores
Currier, Rachel B.; Ulrich, Kathrin; Leroux, Alejandro Ezequiel; Dirdjaja, Natalie; Deambrosi, Matías; Bonilla, Mariana; Ahmed, Yasar Luqman; Adrian, Lorenz; Antelmann, Haike; Jakob, Ursula; Comini, Marcelo A.; Krauth-Siegel, R. Luise
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Most known thioredoxin-type proteins (Trx) participate in redox pathways, using two highly conserved cysteine residues to catalyze thiol-disulfide exchange reactions. Here we demonstrate that the so far unexplored Trx2 from African trypanosomes (Trypanosoma brucei) lacks protein disulfide reductase activity but functions as an effective temperature-activated and redox-regulated chaperone. Immunofluorescence microscopy and fractionated cell lysis revealed that Trx2 is located in the mitochondrion of the parasite. RNA-interference and gene knock-out approaches showed that depletion of Trx2 impairs growth of both mammalian bloodstream and insect stage procyclic parasites. Procyclic cells lacking Trx2 stop proliferation under standard culture conditions at 27°C and are unable to survive prolonged exposure to 37°C, indicating that Trx2 plays a vital role that becomes augmented under heat stress. Moreover, we found that Trx2 contributes to the in vivo infectivity of T. brucei. Remarkably, a Trx2 version, in which all five cysteines were replaced by serine residues, complements for the wildtype protein in conditional knock-out cells and confers parasite infectivity in the mouse model. Characterization of the recombinant protein revealed that Trx2 can coordinate an iron sulfur cluster and is highly sensitive towards spontaneous oxidation. Moreover, we discovered that both wildtype and mutant Trx2 protect other proteins against thermal aggregation and preserve their ability to refold upon return to non-stress conditions. Activation of the chaperone function of Trx2 appears to be triggered by temperature- mediated structural changes and inhibited by oxidative disulfide bond formation. Our studies indicate that Trx2 acts as a novel chaperone in the unique single mitochondrion of T. brucei and reveal a new perspective regarding the physiological function of thioredoxintype proteins in trypanosomes.
Fil: Currier, Rachel B.. Universität Heidelberg; Alemania
Fil: Ulrich, Kathrin. Universität Heidelberg; Alemania. University of Michigan; Estados Unidos
Fil: Leroux, Alejandro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universität Heidelberg; Alemania
Fil: Dirdjaja, Natalie. Universität Heidelberg; Alemania
Fil: Deambrosi, Matías. Instituto Pasteur de Montevideo; Uruguay
Fil: Bonilla, Mariana. Instituto Pasteur de Montevideo; Uruguay
Fil: Ahmed, Yasar Luqman. Universität Heidelberg; Alemania
Fil: Adrian, Lorenz. Technishe Universitat Berlin; Alemania
Fil: Antelmann, Haike. Freie Universität Berlin; Alemania
Fil: Jakob, Ursula. University of Michigan; Estados Unidos
Fil: Comini, Marcelo A.. Instituto Pasteur de Montevideo; Uruguay
Fil: Krauth-Siegel, R. Luise. Universität Heidelberg; Alemania
Materia
Trypanosoma brucei
Thioredoxin
Redox
chaperone
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:11336/124565
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/124565
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperoneCurrier, Rachel B.Ulrich, KathrinLeroux, Alejandro EzequielDirdjaja, NatalieDeambrosi, MatíasBonilla, MarianaAhmed, Yasar LuqmanAdrian, LorenzAntelmann, HaikeJakob, UrsulaComini, Marcelo A.Krauth-Siegel, R. LuiseTrypanosoma bruceiThioredoxinRedoxchaperonehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Most known thioredoxin-type proteins (Trx) participate in redox pathways, using two highly conserved cysteine residues to catalyze thiol-disulfide exchange reactions. Here we demonstrate that the so far unexplored Trx2 from African trypanosomes (Trypanosoma brucei) lacks protein disulfide reductase activity but functions as an effective temperature-activated and redox-regulated chaperone. Immunofluorescence microscopy and fractionated cell lysis revealed that Trx2 is located in the mitochondrion of the parasite. RNA-interference and gene knock-out approaches showed that depletion of Trx2 impairs growth of both mammalian bloodstream and insect stage procyclic parasites. Procyclic cells lacking Trx2 stop proliferation under standard culture conditions at 27°C and are unable to survive prolonged exposure to 37°C, indicating that Trx2 plays a vital role that becomes augmented under heat stress. Moreover, we found that Trx2 contributes to the in vivo infectivity of T. brucei. Remarkably, a Trx2 version, in which all five cysteines were replaced by serine residues, complements for the wildtype protein in conditional knock-out cells and confers parasite infectivity in the mouse model. Characterization of the recombinant protein revealed that Trx2 can coordinate an iron sulfur cluster and is highly sensitive towards spontaneous oxidation. Moreover, we discovered that both wildtype and mutant Trx2 protect other proteins against thermal aggregation and preserve their ability to refold upon return to non-stress conditions. Activation of the chaperone function of Trx2 appears to be triggered by temperature- mediated structural changes and inhibited by oxidative disulfide bond formation. Our studies indicate that Trx2 acts as a novel chaperone in the unique single mitochondrion of T. brucei and reveal a new perspective regarding the physiological function of thioredoxintype proteins in trypanosomes.Fil: Currier, Rachel B.. Universität Heidelberg; AlemaniaFil: Ulrich, Kathrin. Universität Heidelberg; Alemania. University of Michigan; Estados UnidosFil: Leroux, Alejandro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universität Heidelberg; AlemaniaFil: Dirdjaja, Natalie. Universität Heidelberg; AlemaniaFil: Deambrosi, Matías. Instituto Pasteur de Montevideo; UruguayFil: Bonilla, Mariana. Instituto Pasteur de Montevideo; UruguayFil: Ahmed, Yasar Luqman. Universität Heidelberg; AlemaniaFil: Adrian, Lorenz. Technishe Universitat Berlin; AlemaniaFil: Antelmann, Haike. Freie Universität Berlin; AlemaniaFil: Jakob, Ursula. University of Michigan; Estados UnidosFil: Comini, Marcelo A.. Instituto Pasteur de Montevideo; UruguayFil: Krauth-Siegel, R. Luise. Universität Heidelberg; AlemaniaPublic Library of Science2019-09info: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/11336/124565Currier, Rachel B.; Ulrich, Kathrin; Leroux, Alejandro Ezequiel; Dirdjaja, Natalie; Deambrosi, Matías; et al.; An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone; Public Library of Science; Plos Pathogens; 15; 9; 9-2019; 1-361553-7366CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://dx.plos.org/10.1371/journal.ppat.1008065info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1008065info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:23:27Zoai:ri.conicet.gov.ar:11336/124565instacron: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 10:23:27.914CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone
title An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone
spellingShingle An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone
Currier, Rachel B.
Trypanosoma brucei
Thioredoxin
Redox
chaperone
title_short An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone
title_full An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone
title_fullStr An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone
title_full_unstemmed An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone
title_sort An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone
dc.creator.none.fl_str_mv Currier, Rachel B.
Ulrich, Kathrin
Leroux, Alejandro Ezequiel
Dirdjaja, Natalie
Deambrosi, Matías
Bonilla, Mariana
Ahmed, Yasar Luqman
Adrian, Lorenz
Antelmann, Haike
Jakob, Ursula
Comini, Marcelo A.
Krauth-Siegel, R. Luise
author Currier, Rachel B.
author_facet Currier, Rachel B.
Ulrich, Kathrin
Leroux, Alejandro Ezequiel
Dirdjaja, Natalie
Deambrosi, Matías
Bonilla, Mariana
Ahmed, Yasar Luqman
Adrian, Lorenz
Antelmann, Haike
Jakob, Ursula
Comini, Marcelo A.
Krauth-Siegel, R. Luise
author_role author
author2 Ulrich, Kathrin
Leroux, Alejandro Ezequiel
Dirdjaja, Natalie
Deambrosi, Matías
Bonilla, Mariana
Ahmed, Yasar Luqman
Adrian, Lorenz
Antelmann, Haike
Jakob, Ursula
Comini, Marcelo A.
Krauth-Siegel, R. Luise
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Trypanosoma brucei
Thioredoxin
Redox
chaperone
topic Trypanosoma brucei
Thioredoxin
Redox
chaperone
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Most known thioredoxin-type proteins (Trx) participate in redox pathways, using two highly conserved cysteine residues to catalyze thiol-disulfide exchange reactions. Here we demonstrate that the so far unexplored Trx2 from African trypanosomes (Trypanosoma brucei) lacks protein disulfide reductase activity but functions as an effective temperature-activated and redox-regulated chaperone. Immunofluorescence microscopy and fractionated cell lysis revealed that Trx2 is located in the mitochondrion of the parasite. RNA-interference and gene knock-out approaches showed that depletion of Trx2 impairs growth of both mammalian bloodstream and insect stage procyclic parasites. Procyclic cells lacking Trx2 stop proliferation under standard culture conditions at 27°C and are unable to survive prolonged exposure to 37°C, indicating that Trx2 plays a vital role that becomes augmented under heat stress. Moreover, we found that Trx2 contributes to the in vivo infectivity of T. brucei. Remarkably, a Trx2 version, in which all five cysteines were replaced by serine residues, complements for the wildtype protein in conditional knock-out cells and confers parasite infectivity in the mouse model. Characterization of the recombinant protein revealed that Trx2 can coordinate an iron sulfur cluster and is highly sensitive towards spontaneous oxidation. Moreover, we discovered that both wildtype and mutant Trx2 protect other proteins against thermal aggregation and preserve their ability to refold upon return to non-stress conditions. Activation of the chaperone function of Trx2 appears to be triggered by temperature- mediated structural changes and inhibited by oxidative disulfide bond formation. Our studies indicate that Trx2 acts as a novel chaperone in the unique single mitochondrion of T. brucei and reveal a new perspective regarding the physiological function of thioredoxintype proteins in trypanosomes.
Fil: Currier, Rachel B.. Universität Heidelberg; Alemania
Fil: Ulrich, Kathrin. Universität Heidelberg; Alemania. University of Michigan; Estados Unidos
Fil: Leroux, Alejandro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universität Heidelberg; Alemania
Fil: Dirdjaja, Natalie. Universität Heidelberg; Alemania
Fil: Deambrosi, Matías. Instituto Pasteur de Montevideo; Uruguay
Fil: Bonilla, Mariana. Instituto Pasteur de Montevideo; Uruguay
Fil: Ahmed, Yasar Luqman. Universität Heidelberg; Alemania
Fil: Adrian, Lorenz. Technishe Universitat Berlin; Alemania
Fil: Antelmann, Haike. Freie Universität Berlin; Alemania
Fil: Jakob, Ursula. University of Michigan; Estados Unidos
Fil: Comini, Marcelo A.. Instituto Pasteur de Montevideo; Uruguay
Fil: Krauth-Siegel, R. Luise. Universität Heidelberg; Alemania
description Most known thioredoxin-type proteins (Trx) participate in redox pathways, using two highly conserved cysteine residues to catalyze thiol-disulfide exchange reactions. Here we demonstrate that the so far unexplored Trx2 from African trypanosomes (Trypanosoma brucei) lacks protein disulfide reductase activity but functions as an effective temperature-activated and redox-regulated chaperone. Immunofluorescence microscopy and fractionated cell lysis revealed that Trx2 is located in the mitochondrion of the parasite. RNA-interference and gene knock-out approaches showed that depletion of Trx2 impairs growth of both mammalian bloodstream and insect stage procyclic parasites. Procyclic cells lacking Trx2 stop proliferation under standard culture conditions at 27°C and are unable to survive prolonged exposure to 37°C, indicating that Trx2 plays a vital role that becomes augmented under heat stress. Moreover, we found that Trx2 contributes to the in vivo infectivity of T. brucei. Remarkably, a Trx2 version, in which all five cysteines were replaced by serine residues, complements for the wildtype protein in conditional knock-out cells and confers parasite infectivity in the mouse model. Characterization of the recombinant protein revealed that Trx2 can coordinate an iron sulfur cluster and is highly sensitive towards spontaneous oxidation. Moreover, we discovered that both wildtype and mutant Trx2 protect other proteins against thermal aggregation and preserve their ability to refold upon return to non-stress conditions. Activation of the chaperone function of Trx2 appears to be triggered by temperature- mediated structural changes and inhibited by oxidative disulfide bond formation. Our studies indicate that Trx2 acts as a novel chaperone in the unique single mitochondrion of T. brucei and reveal a new perspective regarding the physiological function of thioredoxintype proteins in trypanosomes.
publishDate 2019
dc.date.none.fl_str_mv 2019-09
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/11336/124565
Currier, Rachel B.; Ulrich, Kathrin; Leroux, Alejandro Ezequiel; Dirdjaja, Natalie; Deambrosi, Matías; et al.; An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone; Public Library of Science; Plos Pathogens; 15; 9; 9-2019; 1-36
1553-7366
CONICET Digital
CONICET
url http://hdl.handle.net/11336/124565
identifier_str_mv Currier, Rachel B.; Ulrich, Kathrin; Leroux, Alejandro Ezequiel; Dirdjaja, Natalie; Deambrosi, Matías; et al.; An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone; Public Library of Science; Plos Pathogens; 15; 9; 9-2019; 1-36
1553-7366
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://dx.plos.org/10.1371/journal.ppat.1008065
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1008065
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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score 13.070432

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