Journal
ELIFE
Volume 5, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.11880
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Funding
- Howard Hughes Medical Institute Investigator
- European Molecular Biology Organization Long Term Fellowship
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The membrane-bound transcription factor ATF6 alpha is activated by proteolysis during endoplasmic reticulum (ER) stress. ATF6 alpha target genes encode foldases, chaperones, and lipid biosynthesis enzymes that increase protein-folding capacity in response to demand. The off-state of ATF6 alpha is maintained by its spatial separation in the ER from Golgi-resident proteases that activate it. ER stress induces trafficking of ATF6 alpha. We discovered Ceapins, a class of pyrazole amides, as selective inhibitors of ATF6 alpha signaling that do not inhibit the Golgi proteases or other UPR branches. We show that Ceapins block ATF6 alpha signaling by trapping it in ER-resident foci that are excluded from ER exit sites. Removing the requirement for trafficking by pharmacological elimination of the spatial separation of the ER and Golgi apparatus restored cleavage of ATF6 alpha in the presence of Ceapins. Washout of Ceapins resensitized ATF6 alpha to ER stress. These results suggest that trafficking of ATF6 alpha is regulated by its oligomeric state.
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