Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether
- University of California, San Francisco, United States
- Vanderbilt University, United States
Abstract
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Jonathan S Weissman
Funding
Howard Hughes Medical Institute
- Jonathan S Weissman
- Peter Walter
National Institutes of Health (GM111126)
- Robert M Stroud
National Institutes of Health (DP2 OD021007)
- Martin Kampmann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Elizabeth A Miller, MRC Laboratory of Molecular Biology, United Kingdom
Version history
- Received: March 6, 2019
- Accepted: May 30, 2019
- Accepted Manuscript published: May 31, 2019 (version 1)
- Version of Record published: June 21, 2019 (version 2)
Copyright
© 2019, Torres et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether
eLife 8:e46595.
https://doi.org/10.7554/eLife.46595
