Hurwitz et al. 2022 (PRJNA798445)

General Details

Title The integrated stress response protects microtubule dynamics to recover from proteotoxic stress
Organism
Number of Samples 15
Release Date 2022/01/18 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP355694
ENA SRP355694
GEO GSE193945
BioProject PRJNA798445

Publication

Title
Authors Hurwitz B, Guzzi N, Gola A, Fiore VF, Sendoel A, Nikolova M, Barrows D, Carroll TS, Pasolli HA, Fuchs E
Journal eLife
Publication Date 2022 Jun 27
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. © 2022, Hurwitz, Guzzi et al.
PMC PMC9299849
PMID 35758650
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR17658123 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658122 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658121 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658120 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658119 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658118 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658117 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658116 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658115 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658114 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658113 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658112 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658111 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658110 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
SRR17658109 PRJNA798445 Mus musculus NA_Squamous cell carcinoma Ribo-Seq 0.0
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

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