Sandra Torres1,2, Ciara Gallagher2, Martin Kampmann1, Jonathan Weissman1, Peter Walter2 Departments of Cellular Molecular Pharmacology, and Biochemistry and Biophysics, University of California at San Francisco, and Howard Hughes Medical Institute, San Francisco, CA, USA
The unfolded protein response (UPR) regulates the volume and the protein folding capacity of the endoplasmic reticulum (ER). In response to an imbalance that leads to an accumulation of un- or misfolded proteins, three branches of the UPR sense and transmit the information to drive appropriate gene expression programs to reestablish homeostasis. If this cannot be achieved, cells commit apoptosis. One of the UPR branches is mediated by ATF6α, an ER-tethered transcription factor. Upon trafficking to the Golgi apparatus, ATF6α∍σ χψτοσολιχ δομαιν is severed from its membrane anchor by Golgi-resident proteases and then upregulates genes encoding ER-resident chaperones and folding enzymes. ATF6 plays an essential role in allowing cells to adapt to ER stress, but the events leading to its activation and trafficking remain poorly understood. We recently discovered a series of selective small-molecule ATF6α inhibitors (Ceapins) that trap ATF6α in the ER. A genome-wide CRISPRi screen identified a membrane protein that in the presence of Ceapin prevents ATF6α from exiting the ER. Surprisingly, the Ceapin-mediated retention mechanism may engage inter-organellar junctions.
Funding Acknowledgement: Howard Hughes Medical Institute
Credits: None available.
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