Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis

The EMC complex, a highly conserved transmembrane chaperone in the endoplasmic reticulum (ER), has been associated in humans with sterol homeostasis and a myriad of different cellular activities, rendering the mechanism of EMC functionality enigmatic. Using fission yeast, we demonstrate that the EMC...

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Detalles Bibliográficos
Autores: Berraquero, Modesto, Tallada, Víctor A., Jiménez, Juan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/394891
Acceso en línea:http://hdl.handle.net/10261/394891
Access Level:acceso abierto
Palabra clave:Biochemistry
Molecular biology
Cell biology
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spelling Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesisBerraquero, ModestoTallada, Víctor A.Jiménez, JuanBiochemistryMolecular biologyCell biologyThe EMC complex, a highly conserved transmembrane chaperone in the endoplasmic reticulum (ER), has been associated in humans with sterol homeostasis and a myriad of different cellular activities, rendering the mechanism of EMC functionality enigmatic. Using fission yeast, we demonstrate that the EMC complex facilitates the biogenesis of the sterol transfer protein Lam6/Ltc1 at ER-plasma membrane and ER-mitochondria contact sites. Cells that lose EMC function sequester unfolded Lam6/Ltc1 and other proteins at the mitochondrial matrix, leading to surplus ergosterol, cold-sensitive growth, and mitochondrial dysfunctions. Remarkably, inhibition of ergosterol biosynthesis, but also fluidization of cell membranes to counteract their rigidizing effects, reduce the ER-unfolded protein response and rescue growth and mitochondrial defects in EMC-deficient cells. These results suggest that EMC-assisted biogenesis of Lam6/Ltc1 may provide, through ergosterol homeostasis, optimal membrane fluidity to facilitate biogenesis of other ER-membrane proteins.This work was supported by the Spanish Ministerio de Ciencia e Innovación (grant number PID2019-111124GB-I00 to J.J.).Peer reviewedCell PressMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/394891reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-111124GB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1016/j.isci.2025.112096https://doi.org/10.1016/j.isci.2025.112096Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3948912026-05-22T06:33:51Z
dc.title.none.fl_str_mv Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis
title Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis
spellingShingle Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis
Berraquero, Modesto
Biochemistry
Molecular biology
Cell biology
title_short Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis
title_full Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis
title_fullStr Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis
title_full_unstemmed Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis
title_sort Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis
dc.creator.none.fl_str_mv Berraquero, Modesto
Tallada, Víctor A.
Jiménez, Juan
author Berraquero, Modesto
author_facet Berraquero, Modesto
Tallada, Víctor A.
Jiménez, Juan
author_role author
author2 Tallada, Víctor A.
Jiménez, Juan
author2_role author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Biochemistry
Molecular biology
Cell biology
topic Biochemistry
Molecular biology
Cell biology
description The EMC complex, a highly conserved transmembrane chaperone in the endoplasmic reticulum (ER), has been associated in humans with sterol homeostasis and a myriad of different cellular activities, rendering the mechanism of EMC functionality enigmatic. Using fission yeast, we demonstrate that the EMC complex facilitates the biogenesis of the sterol transfer protein Lam6/Ltc1 at ER-plasma membrane and ER-mitochondria contact sites. Cells that lose EMC function sequester unfolded Lam6/Ltc1 and other proteins at the mitochondrial matrix, leading to surplus ergosterol, cold-sensitive growth, and mitochondrial dysfunctions. Remarkably, inhibition of ergosterol biosynthesis, but also fluidization of cell membranes to counteract their rigidizing effects, reduce the ER-unfolded protein response and rescue growth and mitochondrial defects in EMC-deficient cells. These results suggest that EMC-assisted biogenesis of Lam6/Ltc1 may provide, through ergosterol homeostasis, optimal membrane fluidity to facilitate biogenesis of other ER-membrane proteins.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/394891
url http://hdl.handle.net/10261/394891
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-111124GB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1016/j.isci.2025.112096
https://doi.org/10.1016/j.isci.2025.112096
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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