Work

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

Year: 2016

Type: article

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.

Source: eLife

DOI: 10.7554/elife.15550

Authors: Lars Plate, Christina B Cooley, John J Chen, Ryan J Paxman, Ciara M Gallagher, Franck Madoux, Joseph C Genereux, Wesley Dobbs, Dan Garza, Timothy P Spicer, Louis Scampavia, Steven J Brown, Hugh Rosen, Evan T Powers, Peter Walter, Peter Hodder, R Luke Wiseman, Jeffery W Kelly

Institutions: Scripps Research Institute, Trinity University, Howard Hughes Medical Institute, University of California, San Francisco, Amgen (United States), Jupiter (United States), University of California, Riverside, Proteostasis Therapeutics (United States)

Language: English

Topic: Endoplasmic Reticulum Stress and Disease

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,500

Funders: Leukemia and Lymphoma Society, Amyloidosis Foundation, National Institutes of Health, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke

Awards: Establishing Strategies to Ameliorate Amyloid Pathology in Light Chain Amyloidosis, Exploring the Chemistry and Biology of Arm-Selective UPR Activation, Discovering Small Molecule Activators of Stress-responsive Signaling, Direct Regulation of Extracellular Proteostasis by the Unfolded Protein Response, Discovering Small Molecule Activators of Stress-Responsive Signaling, Probing the biochemical mechanism of amyloid disease, G9000012069, G9000136325, G9000172603, G9000185148, TARGETING ENDOGENOUS SIGNALING PATHWAYS TO AMELIORATE SYSTEMIC AMYLOIDOSES, G9000262906, Probing the biochemical mechanism of amyloid disease

OpenAlex ID: W2476887811

FWCI: 15.61

Cites: 53

Cited by: 234

Related to: 10