Document Type
Article
Publication Date
2016
Abstract
Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases.
DOI
10.7554/eLife.15550.001
Publisher
eLife Sciences Publications Ltd.
City
Cambridge, England
Repository Citation
Plate, L., Cooley, C. B., Chen, J. C., Paxman, R. J., Gallagher, C. M., Madoux, F., ... Kelly, J. W. (2016). Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. eLife, 5, 1-27. https://doi.org/10.7554/eLife.15550
Publication Information
eLife
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.