Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether
| Title: | Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether |
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| Authors: | Sandra Elizabeth Torres, Ciara M Gallagher, Lars Plate, Meghna Gupta, Christina R Liem, Xiaoyan Guo, Ruilin Tian, Robert M Stroud, Martin Kampmann, Jonathan S Weissman, Peter Walter |
| Source: | eLife, Vol 8 (2019) |
| Publisher Information: | eLife Sciences Publications Ltd, 2019. |
| Publication Year: | 2019 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | unfolded protein response, proteostasis, small molecule inhibition, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | The unfolded protein response (UPR) detects and restores deficits in the endoplasmic reticulum (ER) protein folding capacity. Ceapins specifically inhibit the UPR sensor ATF6α, an ER-tethered transcription factor, by retaining it at the ER through an unknown mechanism. Our genome-wide CRISPR interference (CRISPRi) screen reveals that Ceapins function is completely dependent on the ABCD3 peroxisomal transporter. Proteomics studies establish that ABCD3 physically associates with ER-resident ATF6α in cells and in vitro in a Ceapin-dependent manner. Ceapins induce the neomorphic association of ER and peroxisomes by directly tethering the cytosolic domain of ATF6α to ABCD3’s transmembrane regions without inhibiting or depending on ABCD3 transporter activity. Thus, our studies reveal that Ceapins function by chemical-induced misdirection which explains their remarkable specificity and opens up new mechanistic routes for drug development and synthetic biology. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/46595; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.46595 |
| Access URL: | https://doaj.org/article/1385a79477e045e0a8efc889a4a6ac9d |
| Accession Number: | edsdoj.1385a79477e045e0a8efc889a4a6ac9d |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
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| DOI: | 10.7554/eLife.46595 |
| Published in: | eLife |
| Language: | English |