Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

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: http://dx.doi.org/10.7554/eLife.15550.001

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…Similarly, in a more recent work, it was demonstrated that ceapins, a class of pyrazole amides, blocked ATF6 signaling in response to ER stress by trapping it in the ER (126,127). On the other hand, Plate et al identified two nontoxic small molecules, compounds 147 and 263, which selectively activated the ATF6 branch of the UPR (128). They further demonstrate that those compounds reduced secretion and extracellular aggregation of destabilized amyloidogenic proteins (128).…”

“…On the other hand, Plate et al identified two nontoxic small molecules, compounds 147 and 263, which selectively activated the ATF6 branch of the UPR (128). They further demonstrate that those compounds reduced secretion and extracellular aggregation of destabilized amyloidogenic proteins (128). Both approaches, either blocking ATF6 activation or promoting it, may therefore represent useful strategies for controlling ER proteostasis in various human diseases, including cancers.…”

“…The current therapeutic and pharmacological strategies that target ER proteostasis in cancer focus either on exacerbating ER stress to a level with which tumor cells cannot cope and therefore die or on decreasing the adaptive capacity of the tumor cells, leading to loss of selective advantage and tumor death. Over the past 5 years, several inhibitors of the three UPR sensors have been developed (Table 1) (44,58,(126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140). Some new drugs are now tested to specifically target particular UPR sensors to kill cancer cells or sensitize them to commonly used treatments.…”

The unfolded protein response regulator ATF6 promotes mesodermal differentiation

“…Here, we took advantage of the unique ability of stem cells to recapitulate many features of embryogenesis to elucidate the function of ATF6 during human stem cell differentiation. We used a newly identified small-molecule activator of ATF6 to assess how ATF6 signaling affected stem cell differentiation into early germ cell layers and functional cell types (36). Conversely, we examined how impairment of ATF6 signaling affected early human stem cell differentiation using iPSCs generated from patients that were homozygous for loss-of-function ATF6α alleles (11, 27).…”

Unfolded protein response in brain ischemia: A timely update

“…Therefore, UPR has attracted the attention of many biomedical researchers, and small molecules that target UPR for therapeutic purposes have been identified or are under development (for recent reviews, see Hetz et al 40 and Maly and Papa 41 ). Recently, small molecules that target the ATF6 UPR branch with high specificity have been identified, 42,43 and the non-toxic activators of endogenous ATF6 could be of major interest in stroke (see below). In experimental brain ischemia, several strategies have been used to restore ER function impaired by ischemia.…”