Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae

Cellular protein homeostasis relies on a complex network of protein synthesis, folding, sub-cellular localization, and degradation to sustain a functional proteome. Since most of these processes are energy-driven, proteostasis is inescapably afflicted by cellular metabolism. Proteostasis collapse an...

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Detalhes bibliográficos
Autores: Saxena, Kanika, Andersson, Rebecca, Widlund, Per O., Khoomrung, Sakda, Hanzén, Sarah, Nielsen, Jens, Kumar, Navinder, Molin, Mikael, Nyström, Thomas
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/222782
Acesso em linha:https://hdl.handle.net/2445/222782
Access Level:acceso abierto
Palavra-chave:Saccharomyces cerevisiae
Metabolisme de proteïnes
Protein metabolism
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spelling Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiaeSaxena, KanikaAndersson, RebeccaWidlund, Per O.Khoomrung, SakdaHanzén, SarahNielsen, JensKumar, NavinderMolin, MikaelNyström, ThomasSaccharomyces cerevisiaeMetabolisme de proteïnesSaccharomyces cerevisiaeProtein metabolismCellular protein homeostasis relies on a complex network of protein synthesis, folding, sub-cellular localization, and degradation to sustain a functional proteome. Since most of these processes are energy-driven, proteostasis is inescapably afflicted by cellular metabolism. Proteostasis collapse and metabolic imbalance are both linked to aging and age-associated disorders, yet they have traditionally been studied as separate phenomena in the context of aging. In this study, we indicate that reduced proteostasis capacity is a result of a metabolic imbalance associated with age. We observed increased accumulation of L-serine and L-threonine in replicative old cells of Saccharomyces cerevisiae, indicating an imbalance in amino acid metabolism with replicative aging. Replicating this metabolic imbalance in young cells through deletion of serine-dependent transcriptional activator, CHA4, resulted in increased aggregation of endogenous proteins along with misfolding-prone proteins Guk1-7ts-GFP and Luciferase-GFP in both young and old cells. Aggregate formation in the cha4D strain required a functional sensor of mitochondrial dysfunction and an activator of the retrograde signaling gene, RTG2. CHA4 and RTG2 exhibited genetic interaction and together regulated mitochondrial metabolism, replicative lifespan, and aggregate formation in young cells, connecting metabolic regulation with proteostasis and aging. Constitutive activation of retrograde signaling through overexpression of RTG2 or deletion of MKS-1, a negative regulator of Rtg1-Rtg3 nuclear translocation, resulted in faster resolution of aggregates upon heat shock through RTG3 and was found to be independent of molecular chaperone upregulation.Elsevier BV2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/222782Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.jbc.2025.110329Journal of Biological Chemistry, 2025, vol. 301, num. 7, 110329https://doi.org/10.1016/j.jbc.2025.110329cc-by (c) Saxena, Kanika et al., 2025http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2227822026-05-27T06:46:51Z
dc.title.none.fl_str_mv Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae
title Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae
spellingShingle Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae
Saxena, Kanika
Saccharomyces cerevisiae
Metabolisme de proteïnes
Saccharomyces cerevisiae
Protein metabolism
title_short Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae
title_full Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae
title_fullStr Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae
title_full_unstemmed Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae
title_sort Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae
dc.creator.none.fl_str_mv Saxena, Kanika
Andersson, Rebecca
Widlund, Per O.
Khoomrung, Sakda
Hanzén, Sarah
Nielsen, Jens
Kumar, Navinder
Molin, Mikael
Nyström, Thomas
author Saxena, Kanika
author_facet Saxena, Kanika
Andersson, Rebecca
Widlund, Per O.
Khoomrung, Sakda
Hanzén, Sarah
Nielsen, Jens
Kumar, Navinder
Molin, Mikael
Nyström, Thomas
author_role author
author2 Andersson, Rebecca
Widlund, Per O.
Khoomrung, Sakda
Hanzén, Sarah
Nielsen, Jens
Kumar, Navinder
Molin, Mikael
Nyström, Thomas
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Saccharomyces cerevisiae
Metabolisme de proteïnes
Saccharomyces cerevisiae
Protein metabolism
topic Saccharomyces cerevisiae
Metabolisme de proteïnes
Saccharomyces cerevisiae
Protein metabolism
description Cellular protein homeostasis relies on a complex network of protein synthesis, folding, sub-cellular localization, and degradation to sustain a functional proteome. Since most of these processes are energy-driven, proteostasis is inescapably afflicted by cellular metabolism. Proteostasis collapse and metabolic imbalance are both linked to aging and age-associated disorders, yet they have traditionally been studied as separate phenomena in the context of aging. In this study, we indicate that reduced proteostasis capacity is a result of a metabolic imbalance associated with age. We observed increased accumulation of L-serine and L-threonine in replicative old cells of Saccharomyces cerevisiae, indicating an imbalance in amino acid metabolism with replicative aging. Replicating this metabolic imbalance in young cells through deletion of serine-dependent transcriptional activator, CHA4, resulted in increased aggregation of endogenous proteins along with misfolding-prone proteins Guk1-7ts-GFP and Luciferase-GFP in both young and old cells. Aggregate formation in the cha4D strain required a functional sensor of mitochondrial dysfunction and an activator of the retrograde signaling gene, RTG2. CHA4 and RTG2 exhibited genetic interaction and together regulated mitochondrial metabolism, replicative lifespan, and aggregate formation in young cells, connecting metabolic regulation with proteostasis and aging. Constitutive activation of retrograde signaling through overexpression of RTG2 or deletion of MKS-1, a negative regulator of Rtg1-Rtg3 nuclear translocation, resulted in faster resolution of aggregates upon heat shock through RTG3 and was found to be independent of molecular chaperone upregulation.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/222782
url https://hdl.handle.net/2445/222782
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.jbc.2025.110329
Journal of Biological Chemistry, 2025, vol. 301, num. 7, 110329
https://doi.org/10.1016/j.jbc.2025.110329
dc.rights.none.fl_str_mv cc-by (c) Saxena, Kanika et al., 2025
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Saxena, Kanika et al., 2025
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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