TY - JOUR TI - Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation AU - Plate, Lars AU - Cooley, Christina B AU - Chen, John J AU - Paxman, Ryan J AU - Gallagher, Ciara M AU - Madoux, Franck AU - Genereux, Joseph C AU - Dobbs, Wesley AU - Garza, Dan AU - Spicer, Timothy P AU - Scampavia, Louis AU - Brown, Steven J AU - Rosen, Hugh AU - Powers, Evan T AU - Walter, Peter AU - Hodder, Peter AU - Wiseman, R Luke AU - Kelly, Jeffery W A2 - Ng, Davis VL - 5 PY - 2016 DA - 2016/07/20 SP - e15550 C1 - eLife 2016;5:e15550 DO - 10.7554/eLife.15550 UR - https://doi.org/10.7554/eLife.15550 AB - 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. KW - patient-derived plasma cells KW - HEK293 cells KW - HepG2 cells KW - mouse embryonic fibroblasts JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -