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The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress

Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dis...

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Autores principales: Hurwitz, Brian, Guzzi, Nicola, Gola, Anita, Fiore, Vincent F, Sendoel, Ataman, Nikolova, Maria, Barrows, Douglas, Carroll, Thomas S, Pasolli, H Amalia, Fuchs, Elaine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299849/
https://www.ncbi.nlm.nih.gov/pubmed/35758650
http://dx.doi.org/10.7554/eLife.77780
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author Hurwitz, Brian
Guzzi, Nicola
Gola, Anita
Fiore, Vincent F
Sendoel, Ataman
Nikolova, Maria
Barrows, Douglas
Carroll, Thomas S
Pasolli, H Amalia
Fuchs, Elaine
author_facet Hurwitz, Brian
Guzzi, Nicola
Gola, Anita
Fiore, Vincent F
Sendoel, Ataman
Nikolova, Maria
Barrows, Douglas
Carroll, Thomas S
Pasolli, H Amalia
Fuchs, Elaine
author_sort Hurwitz, Brian
collection PubMed
description Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely, the S51 phosphorylation site of eukaryotic translation initiation factor eIF2α and genetically replaced eIF2α with eIF2α-S51A in mouse squamous cell carcinoma (SCC) stem cells of skin. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule-organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during proteotoxic stress, the ISR also functions in promoting cellular recovery once the stress has subsided. Remarkably, this molecular program is unique to transformed skin stem cells, hence exposing a vulnerability in cancer that could be exploited therapeutically.
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spelling pubmed-92998492022-07-21 The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress Hurwitz, Brian Guzzi, Nicola Gola, Anita Fiore, Vincent F Sendoel, Ataman Nikolova, Maria Barrows, Douglas Carroll, Thomas S Pasolli, H Amalia Fuchs, Elaine eLife Cancer Biology Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely, the S51 phosphorylation site of eukaryotic translation initiation factor eIF2α and genetically replaced eIF2α with eIF2α-S51A in mouse squamous cell carcinoma (SCC) stem cells of skin. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule-organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during proteotoxic stress, the ISR also functions in promoting cellular recovery once the stress has subsided. Remarkably, this molecular program is unique to transformed skin stem cells, hence exposing a vulnerability in cancer that could be exploited therapeutically. eLife Sciences Publications, Ltd 2022-06-27 /pmc/articles/PMC9299849/ /pubmed/35758650 http://dx.doi.org/10.7554/eLife.77780 Text en © 2022, Hurwitz, Guzzi 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 Cancer Biology
Hurwitz, Brian
Guzzi, Nicola
Gola, Anita
Fiore, Vincent F
Sendoel, Ataman
Nikolova, Maria
Barrows, Douglas
Carroll, Thomas S
Pasolli, H Amalia
Fuchs, Elaine
The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress
title The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress
title_full The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress
title_fullStr The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress
title_full_unstemmed The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress
title_short The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress
title_sort integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299849/
https://www.ncbi.nlm.nih.gov/pubmed/35758650
http://dx.doi.org/10.7554/eLife.77780
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