Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions

Autores
Capmany, Anahi; Abregú, Ángel Julián; Alonso Bivou, Mariano Ángel; Damiani, María T.
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Chlamydia trachomatis, an obligate intracellular bacterium, intercepts different trafficking pathways of the host cell to acquire essential lipids for its survival and replication, particularly from the Golgi apparatus via a Rab14-mediated transport. Molecular mechanisms underlying how these bacteria manipulate intracellular transport are a matter of intense study. Here, we show that C. trachomatis utilizes Akt/AS160 signaling pathway to promote sphingolipids delivery to the chlamydial inclusion through Rab14-controlled vesicular transport. C. trachomatis provokes Akt phosphorylation along its entire developmental life cycle and recruits phosphorylated Akt (pAkt) to the inclusion membrane. As a consequence, Akt Substrate of 160 kDa (AS160), also known as TBC1D4, a GTPase Activating Protein (GAP) for Rab14, is phosphorylated and therefore inactivated. Phosphorylated AS160 (pAS160) loses its ability to promote GTP hydrolysis, favoring Rab14 binding to GTP. Akt inhibition by an allosteric isoform-specific Akt inhibitor (iAkt) prevents AS160 phosphorylation and reduces Rab14 recruitment to chlamydial inclusions. iAkt further impairs sphingolipids acquisition by C. trachomatis-inclusion and provokes lipid retention at the Golgi apparatus. Consequently, treatment with iAkt decreases chlamydial inclusion size, bacterial multiplication, and infectivity in a dose-dependent manner. Similar results were found in AS160-depleted cells. By electron microscopy, we observed that iAkt generates abnormal bacterial forms as those reported after sphingolipids deprivation or Rab14 silencing. Taken together, our findings indicate that targeting the Akt/AS160/Rab14 axis could constitute a novel strategy to limit chlamydial infections, mainly for those caused by antibiotic-resistant bacteria.
Fil: Capmany, Anahi. Universidad de Mendoza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Abregú, Ángel Julián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Alonso Bivou, Mariano Ángel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Damiani, María T.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Materia
AKT/AS160 SIGNALING PATHWAY
CHLAMYDIA TRACHOMATIS
GOLGI-DERIVED SPHINGOLIPIDS
GTPASE ACTIVATING PROTEINS
RAB PROTEINS
RAB14
VESICULAR TRANSPORT
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:11336/124078
Acceder
id CONICETDig_ed8d6cea070f65291d7dba54955081c6
oai_identifier_str oai:ri.conicet.gov.ar:11336/124078
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusionsCapmany, AnahiAbregú, Ángel JuliánAlonso Bivou, Mariano ÁngelDamiani, María T.AKT/AS160 SIGNALING PATHWAYCHLAMYDIA TRACHOMATISGOLGI-DERIVED SPHINGOLIPIDSGTPASE ACTIVATING PROTEINSRAB PROTEINSRAB14VESICULAR TRANSPORThttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Chlamydia trachomatis, an obligate intracellular bacterium, intercepts different trafficking pathways of the host cell to acquire essential lipids for its survival and replication, particularly from the Golgi apparatus via a Rab14-mediated transport. Molecular mechanisms underlying how these bacteria manipulate intracellular transport are a matter of intense study. Here, we show that C. trachomatis utilizes Akt/AS160 signaling pathway to promote sphingolipids delivery to the chlamydial inclusion through Rab14-controlled vesicular transport. C. trachomatis provokes Akt phosphorylation along its entire developmental life cycle and recruits phosphorylated Akt (pAkt) to the inclusion membrane. As a consequence, Akt Substrate of 160 kDa (AS160), also known as TBC1D4, a GTPase Activating Protein (GAP) for Rab14, is phosphorylated and therefore inactivated. Phosphorylated AS160 (pAS160) loses its ability to promote GTP hydrolysis, favoring Rab14 binding to GTP. Akt inhibition by an allosteric isoform-specific Akt inhibitor (iAkt) prevents AS160 phosphorylation and reduces Rab14 recruitment to chlamydial inclusions. iAkt further impairs sphingolipids acquisition by C. trachomatis-inclusion and provokes lipid retention at the Golgi apparatus. Consequently, treatment with iAkt decreases chlamydial inclusion size, bacterial multiplication, and infectivity in a dose-dependent manner. Similar results were found in AS160-depleted cells. By electron microscopy, we observed that iAkt generates abnormal bacterial forms as those reported after sphingolipids deprivation or Rab14 silencing. Taken together, our findings indicate that targeting the Akt/AS160/Rab14 axis could constitute a novel strategy to limit chlamydial infections, mainly for those caused by antibiotic-resistant bacteria.Fil: Capmany, Anahi. Universidad de Mendoza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Abregú, Ángel Julián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Alonso Bivou, Mariano Ángel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Damiani, María T.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFrontiers Media S.A.2019-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/124078Capmany, Anahi; Abregú, Ángel Julián; Alonso Bivou, Mariano Ángel; Damiani, María T.; Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions; Frontiers Media S.A.; Frontiers in Microbiology; 10; APR; 4-2019; 1-211664-302XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/article/10.3389/fmicb.2019.00666/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fmicb.2019.00666info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:51:42Zoai:ri.conicet.gov.ar:11336/124078instacron: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:34982025-09-03 09:51:42.508CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions
title Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions
spellingShingle Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions
Capmany, Anahi
AKT/AS160 SIGNALING PATHWAY
CHLAMYDIA TRACHOMATIS
GOLGI-DERIVED SPHINGOLIPIDS
GTPASE ACTIVATING PROTEINS
RAB PROTEINS
RAB14
VESICULAR TRANSPORT
title_short Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions
title_full Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions
title_fullStr Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions
title_full_unstemmed Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions
title_sort Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions
dc.creator.none.fl_str_mv Capmany, Anahi
Abregú, Ángel Julián
Alonso Bivou, Mariano Ángel
Damiani, María T.
author Capmany, Anahi
author_facet Capmany, Anahi
Abregú, Ángel Julián
Alonso Bivou, Mariano Ángel
Damiani, María T.
author_role author
author2 Abregú, Ángel Julián
Alonso Bivou, Mariano Ángel
Damiani, María T.
author2_role author
author
author
dc.subject.none.fl_str_mv AKT/AS160 SIGNALING PATHWAY
CHLAMYDIA TRACHOMATIS
GOLGI-DERIVED SPHINGOLIPIDS
GTPASE ACTIVATING PROTEINS
RAB PROTEINS
RAB14
VESICULAR TRANSPORT
topic AKT/AS160 SIGNALING PATHWAY
CHLAMYDIA TRACHOMATIS
GOLGI-DERIVED SPHINGOLIPIDS
GTPASE ACTIVATING PROTEINS
RAB PROTEINS
RAB14
VESICULAR TRANSPORT
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Chlamydia trachomatis, an obligate intracellular bacterium, intercepts different trafficking pathways of the host cell to acquire essential lipids for its survival and replication, particularly from the Golgi apparatus via a Rab14-mediated transport. Molecular mechanisms underlying how these bacteria manipulate intracellular transport are a matter of intense study. Here, we show that C. trachomatis utilizes Akt/AS160 signaling pathway to promote sphingolipids delivery to the chlamydial inclusion through Rab14-controlled vesicular transport. C. trachomatis provokes Akt phosphorylation along its entire developmental life cycle and recruits phosphorylated Akt (pAkt) to the inclusion membrane. As a consequence, Akt Substrate of 160 kDa (AS160), also known as TBC1D4, a GTPase Activating Protein (GAP) for Rab14, is phosphorylated and therefore inactivated. Phosphorylated AS160 (pAS160) loses its ability to promote GTP hydrolysis, favoring Rab14 binding to GTP. Akt inhibition by an allosteric isoform-specific Akt inhibitor (iAkt) prevents AS160 phosphorylation and reduces Rab14 recruitment to chlamydial inclusions. iAkt further impairs sphingolipids acquisition by C. trachomatis-inclusion and provokes lipid retention at the Golgi apparatus. Consequently, treatment with iAkt decreases chlamydial inclusion size, bacterial multiplication, and infectivity in a dose-dependent manner. Similar results were found in AS160-depleted cells. By electron microscopy, we observed that iAkt generates abnormal bacterial forms as those reported after sphingolipids deprivation or Rab14 silencing. Taken together, our findings indicate that targeting the Akt/AS160/Rab14 axis could constitute a novel strategy to limit chlamydial infections, mainly for those caused by antibiotic-resistant bacteria.
Fil: Capmany, Anahi. Universidad de Mendoza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Abregú, Ángel Julián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Alonso Bivou, Mariano Ángel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Damiani, María T.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
description Chlamydia trachomatis, an obligate intracellular bacterium, intercepts different trafficking pathways of the host cell to acquire essential lipids for its survival and replication, particularly from the Golgi apparatus via a Rab14-mediated transport. Molecular mechanisms underlying how these bacteria manipulate intracellular transport are a matter of intense study. Here, we show that C. trachomatis utilizes Akt/AS160 signaling pathway to promote sphingolipids delivery to the chlamydial inclusion through Rab14-controlled vesicular transport. C. trachomatis provokes Akt phosphorylation along its entire developmental life cycle and recruits phosphorylated Akt (pAkt) to the inclusion membrane. As a consequence, Akt Substrate of 160 kDa (AS160), also known as TBC1D4, a GTPase Activating Protein (GAP) for Rab14, is phosphorylated and therefore inactivated. Phosphorylated AS160 (pAS160) loses its ability to promote GTP hydrolysis, favoring Rab14 binding to GTP. Akt inhibition by an allosteric isoform-specific Akt inhibitor (iAkt) prevents AS160 phosphorylation and reduces Rab14 recruitment to chlamydial inclusions. iAkt further impairs sphingolipids acquisition by C. trachomatis-inclusion and provokes lipid retention at the Golgi apparatus. Consequently, treatment with iAkt decreases chlamydial inclusion size, bacterial multiplication, and infectivity in a dose-dependent manner. Similar results were found in AS160-depleted cells. By electron microscopy, we observed that iAkt generates abnormal bacterial forms as those reported after sphingolipids deprivation or Rab14 silencing. Taken together, our findings indicate that targeting the Akt/AS160/Rab14 axis could constitute a novel strategy to limit chlamydial infections, mainly for those caused by antibiotic-resistant bacteria.
publishDate 2019
dc.date.none.fl_str_mv 2019-04
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/11336/124078
Capmany, Anahi; Abregú, Ángel Julián; Alonso Bivou, Mariano Ángel; Damiani, María T.; Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions; Frontiers Media S.A.; Frontiers in Microbiology; 10; APR; 4-2019; 1-21
1664-302X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/124078
identifier_str_mv Capmany, Anahi; Abregú, Ángel Julián; Alonso Bivou, Mariano Ángel; Damiani, María T.; Akt/AS160 Signaling pathway inhibition impairs infection by decreasing rab14-controlled sphingolipids delivery to chlamydial inclusions; Frontiers Media S.A.; Frontiers in Microbiology; 10; APR; 4-2019; 1-21
1664-302X
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://www.frontiersin.org/article/10.3389/fmicb.2019.00666/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fmicb.2019.00666
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
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media S.A.
publisher.none.fl_str_mv Frontiers Media S.A.
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 13.13397

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