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Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Here, we use chemical inhibitors targeting discrete steps of translation to compare how lowering the concentration of all or only translation initiation-dependent proteins rescues Caenorhabditis...

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Autores principales: Clay, Khalyd J, Yang, Yongzhi, Clark, Christina, Petrascheck, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10581687/
https://www.ncbi.nlm.nih.gov/pubmed/37795690
http://dx.doi.org/10.7554/eLife.76465
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author Clay, Khalyd J
Yang, Yongzhi
Clark, Christina
Petrascheck, Michael
author_facet Clay, Khalyd J
Yang, Yongzhi
Clark, Christina
Petrascheck, Michael
author_sort Clay, Khalyd J
collection PubMed
description Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Here, we use chemical inhibitors targeting discrete steps of translation to compare how lowering the concentration of all or only translation initiation-dependent proteins rescues Caenorhabditis elegans from proteotoxic stress. We systematically challenge proteostasis and show that pharmacologically inhibiting translation initiation or elongation elicits a distinct protective profile. Inhibiting elongation protects from heat and proteasome dysfunction independently from HSF-1 but does not protect from age-associated protein aggregation. Conversely, inhibition of initiation protects from heat and age-associated protein aggregation and increases lifespan, dependent on hsf-1, but does not protect from proteotoxicity caused by proteasome dysfunction. Surprisingly, we find that the ability of the translation initiation machinery to control the concentration of newly synthesized proteins depends on HSF-1. Inhibition of translation initiation in wild-type animals reduces the concentration of newly synthesized proteins but increases it in hsf-1 mutants. Our findings suggest that the HSF-1 pathway is not only a downstream target of translation but also directly cooperates with the translation initiation machinery to control the concentration of newly synthesized proteins to restore proteostasis.
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spelling pubmed-105816872023-10-18 Proteostasis is differentially modulated by inhibition of translation initiation or elongation Clay, Khalyd J Yang, Yongzhi Clark, Christina Petrascheck, Michael eLife Biochemistry and Chemical Biology Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Here, we use chemical inhibitors targeting discrete steps of translation to compare how lowering the concentration of all or only translation initiation-dependent proteins rescues Caenorhabditis elegans from proteotoxic stress. We systematically challenge proteostasis and show that pharmacologically inhibiting translation initiation or elongation elicits a distinct protective profile. Inhibiting elongation protects from heat and proteasome dysfunction independently from HSF-1 but does not protect from age-associated protein aggregation. Conversely, inhibition of initiation protects from heat and age-associated protein aggregation and increases lifespan, dependent on hsf-1, but does not protect from proteotoxicity caused by proteasome dysfunction. Surprisingly, we find that the ability of the translation initiation machinery to control the concentration of newly synthesized proteins depends on HSF-1. Inhibition of translation initiation in wild-type animals reduces the concentration of newly synthesized proteins but increases it in hsf-1 mutants. Our findings suggest that the HSF-1 pathway is not only a downstream target of translation but also directly cooperates with the translation initiation machinery to control the concentration of newly synthesized proteins to restore proteostasis. eLife Sciences Publications, Ltd 2023-10-05 /pmc/articles/PMC10581687/ /pubmed/37795690 http://dx.doi.org/10.7554/eLife.76465 Text en © 2023, Clay et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Clay, Khalyd J
Yang, Yongzhi
Clark, Christina
Petrascheck, Michael
Proteostasis is differentially modulated by inhibition of translation initiation or elongation
title Proteostasis is differentially modulated by inhibition of translation initiation or elongation
title_full Proteostasis is differentially modulated by inhibition of translation initiation or elongation
title_fullStr Proteostasis is differentially modulated by inhibition of translation initiation or elongation
title_full_unstemmed Proteostasis is differentially modulated by inhibition of translation initiation or elongation
title_short Proteostasis is differentially modulated by inhibition of translation initiation or elongation
title_sort proteostasis is differentially modulated by inhibition of translation initiation or elongation
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10581687/
https://www.ncbi.nlm.nih.gov/pubmed/37795690
http://dx.doi.org/10.7554/eLife.76465
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AT petrascheckmichael proteostasisisdifferentiallymodulatedbyinhibitionoftranslationinitiationorelongation