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| Status |
Public on Apr 14, 2021 |
| Title |
Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2a via the Hsp70-Bag3 module. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The major heat shock protein Hsp70 has been shown to form a complex with a scaffold protein Bag3, linking it to multiple signaling pathways. Via these interactions, the Hsp70-Bag3 module functions as a proteotoxicity sensor that controls cell signaling. Here, as a tool to identify signaling pathways regulated by this complex, we utilized JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3. Gene expression profiling followed by the pathway analysis indicated that a set of signaling pathways including the unfolded protein response (UPR) was activated by JG-98. Surprisingly, only the translation initiation factor eIF2a-associated branch of the UPR was activated under these conditions, while other UPR branches mediating induction of ER chaperones were not induced, suggesting that the response was not related to ER proteotoxicity and thus to ER-associated kinase PERK1. Indeed, induction of the UPR genes under these conditions was dependent on activation of a distinct cytoplasmic eIF2a kinase, HRI. We demonstrated that the Hsp70-Bag3 complex directly interacted with HRI and regulated phosphorylation of eIF2a upon induction of cytoplasmic proteotoxicity. Therefore, we uncovered a novel signaling response, which regulates cell death upon the buildup of abnormal protein species in cytoplasm via an Hsp70-Bag3-HRI-eIF2a axis.
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| Overall design |
Comparison of sensitivity to JG-98, Hsp70 inhibitor on transformed cells.
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| Contributor(s) |
Patel S, Kumar S, Baldan S, Hesin A, Yaglom J, Sherman MY |
| Citation(s) |
35573186 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA081244 |
Heat shock proteins in signaling and cancer |
BOSTON UNIVERSITY |
Michael Y Sherman |
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| Submission date |
Apr 04, 2021 |
| Last update date |
May 17, 2022 |
| Contact name |
Shivani Patel |
| E-mail(s) |
patel.shiva2593@gmail.com, shivanip@ariel.ac.il
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| Organization name |
Ariel University
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| Department |
Molecular Biology
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| Lab |
Cancer Biology laboratory
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| Street address |
65, Ramat Hagolan
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| City |
Ariel |
| State/province |
IL |
| ZIP/Postal code |
40700 |
| Country |
Israel |
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| Platforms (1) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA719638 |
| SRA |
SRP313383 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE171440_ETEC_geneset.csv.gz |
713.5 Kb |
(ftp)(http) |
CSV |
| GSE171440_NTNC_geneset.csv.gz |
721.4 Kb |
(ftp)(http) |
CSV |
| GSE171440_featurecounts_NeuTvsEmpty.txt.gz |
5.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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