Title | The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Hurwitz B, Guzzi N, Gola A, Fiore VF, Sendoel A, Nikolova M, Barrows D, Carroll TS, H Pasolli A, Fuchs E |
Journal | Elife |
Volume | 11 |
Date Published | 2022 Jun 27 |
ISSN | 2050-084X |
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. |
DOI | 10.7554/eLife.77780 |
Alternate Journal | Elife |
PubMed ID | 35758650 |
Grant List | F30CA236239 / / 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 |
Submitted by bel2021 on July 21, 2022 - 2:17pm