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

TitleThe integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress.
Publication TypeJournal Article
Year of Publication2022
AuthorsHurwitz B, Guzzi N, Gola A, Fiore VF, Sendoel A, Nikolova M, Barrows D, Carroll TS, H Pasolli A, Fuchs E
JournalElife
Volume11
Date Published2022 Jun 27
ISSN2050-084X
Abstract

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.

DOI10.7554/eLife.77780
Alternate JournalElife
PubMed ID35758650
Grant ListF30CA236239 / / Ruth Kirschstein NIH Predoctoral Fellow /
T32GM007739 / / Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional Medical Scientist Training Program /
DRG 2409-20 / / Damon Runyon Cancer Research Foundation National Mah Jongg League Fellowship /
R01-AR27883 / NH / NIH HHS / United States
Jane Coffin Childs Associate / HHMI / Howard Hughes Medical Institute / United States
National Mah Jongg League Fellowship (DRG 2409-20) / DRCRF / Damon Runyon Cancer Research Foundation / United States
R01-AR27883 / NH / NIH HHS / United States

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