Proteostasis is differentially modulated by inhibition of translation initiation or elongation

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Abstract

Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Here, we use chemical inhibitors targeting discreet 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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All data generated or analysed during this study are included in the manuscript and supporting file.

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Khalyd J Clay

Department of Molecular Medicine, Scripps Research Institute, La Jolla, United States

Competing interests
Khalyd J Clay, is a scientific founder and advisor to Cyclone Therapeutics, Inc., a biotech company developing therapeutics targeting translation..

"This ORCID iD identifies the author of this article:" 0000-0003-1381-5295
Yongzhi Yang

Department of Molecular Medicine, Scripps Research Institute, La Jolla, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-9713-0009
Christina Clark

Department of Molecular Medicine, Scripps Research Institute, La Jolla, United States

Competing interests
No competing interests declared.
Michael Petrascheck

Department of Molecular Medicine, Scripps Research Institute, La Jolla, United States

For correspondence
pscheck@scripps.edu

Competing interests
Michael Petrascheck, is a scientific founder and advisor to Cyclone Therapeutics, Inc., a biotech company developing therapeutics targeting translation..

"This ORCID iD identifies the author of this article:" 0000-0002-1010-145X

Funding

National Institutes of Health (R21NS107951)

Michael Petrascheck

National Institute on Aging (R01AG067331)

Michael Petrascheck

The Glenn Foundation

Michael Petrascheck

Dorris Neuroscience Scholar Fellowship

Khalyd J Clay

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.