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Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells

Cells respond to stress by synthesizing chaperone proteins that seek to correct protein misfolding and maintain function. However, abrogation of protein homeostasis is a hallmark of aging, leading to loss of function and the formation of proteotoxic aggregates characteristic of pathology. Consequent...

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Autores principales: Llewellyn, Jack, Mallikarjun, Venkatesh, Appleton, Ellen, Osipova, Maria, Gilbert, Hamish T. J., Richardson, Stephen M., Hubbard, Simon J., Swift, Joe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10083568/
https://www.ncbi.nlm.nih.gov/pubmed/36989307
http://dx.doi.org/10.1073/pnas.2210745120
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author Llewellyn, Jack
Mallikarjun, Venkatesh
Appleton, Ellen
Osipova, Maria
Gilbert, Hamish T. J.
Richardson, Stephen M.
Hubbard, Simon J.
Swift, Joe
author_facet Llewellyn, Jack
Mallikarjun, Venkatesh
Appleton, Ellen
Osipova, Maria
Gilbert, Hamish T. J.
Richardson, Stephen M.
Hubbard, Simon J.
Swift, Joe
author_sort Llewellyn, Jack
collection PubMed
description Cells respond to stress by synthesizing chaperone proteins that seek to correct protein misfolding and maintain function. However, abrogation of protein homeostasis is a hallmark of aging, leading to loss of function and the formation of proteotoxic aggregates characteristic of pathology. Consequently, discovering the underlying molecular causes of this deterioration in proteostasis is key to designing effective interventions to disease or to maintaining cell health in regenerative medicine strategies. Here, we examined primary human mesenchymal stem cells, cultured to a point of replicative senescence and subjected to heat shock, as an in vitro model of the aging stress response. Multi -omics analysis showed how homeostasis components were reduced in senescent cells, caused by dysregulation of a functional network of chaperones, thereby limiting proteostatic competence. Time-resolved analysis of the primary response factors, including those regulating heat shock protein 70 kDa (HSPA1A), revealed that regulatory control is essentially translational. Senescent cells have a reduced capacity for chaperone protein translation and misfolded protein (MFP) turnover, driven by downregulation of ribosomal proteins and loss of the E3 ubiquitin ligase CHIP (C-terminus of HSP70 interacting protein) which marks MFPs for degradation. This limits the cell’s stress response and subsequent recovery. A kinetic model recapitulated these reduced capacities and predicted an accumulation of MFP, a hypothesis supported by evidence of systematic changes to the proteomic fold state. These results thus establish a specific loss of regulatory capacity at the protein, rather than transcript, level and uncover underlying systematic links between aging and loss of protein homeostasis.
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spelling pubmed-100835682023-04-11 Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells Llewellyn, Jack Mallikarjun, Venkatesh Appleton, Ellen Osipova, Maria Gilbert, Hamish T. J. Richardson, Stephen M. Hubbard, Simon J. Swift, Joe Proc Natl Acad Sci U S A Biological Sciences Cells respond to stress by synthesizing chaperone proteins that seek to correct protein misfolding and maintain function. However, abrogation of protein homeostasis is a hallmark of aging, leading to loss of function and the formation of proteotoxic aggregates characteristic of pathology. Consequently, discovering the underlying molecular causes of this deterioration in proteostasis is key to designing effective interventions to disease or to maintaining cell health in regenerative medicine strategies. Here, we examined primary human mesenchymal stem cells, cultured to a point of replicative senescence and subjected to heat shock, as an in vitro model of the aging stress response. Multi -omics analysis showed how homeostasis components were reduced in senescent cells, caused by dysregulation of a functional network of chaperones, thereby limiting proteostatic competence. Time-resolved analysis of the primary response factors, including those regulating heat shock protein 70 kDa (HSPA1A), revealed that regulatory control is essentially translational. Senescent cells have a reduced capacity for chaperone protein translation and misfolded protein (MFP) turnover, driven by downregulation of ribosomal proteins and loss of the E3 ubiquitin ligase CHIP (C-terminus of HSP70 interacting protein) which marks MFPs for degradation. This limits the cell’s stress response and subsequent recovery. A kinetic model recapitulated these reduced capacities and predicted an accumulation of MFP, a hypothesis supported by evidence of systematic changes to the proteomic fold state. These results thus establish a specific loss of regulatory capacity at the protein, rather than transcript, level and uncover underlying systematic links between aging and loss of protein homeostasis. National Academy of Sciences 2023-03-29 2023-04-04 /pmc/articles/PMC10083568/ /pubmed/36989307 http://dx.doi.org/10.1073/pnas.2210745120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Llewellyn, Jack
Mallikarjun, Venkatesh
Appleton, Ellen
Osipova, Maria
Gilbert, Hamish T. J.
Richardson, Stephen M.
Hubbard, Simon J.
Swift, Joe
Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells
title Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells
title_full Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells
title_fullStr Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells
title_full_unstemmed Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells
title_short Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells
title_sort loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10083568/
https://www.ncbi.nlm.nih.gov/pubmed/36989307
http://dx.doi.org/10.1073/pnas.2210745120
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