title: 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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.
authors.forename: Lars
authors.identifier: 0000-0003-4363-6116
authors.initials: L
authors.lastname: Plate
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.
authors.forename: Christina B
authors.identifier: 0000-0001-9699-7682
authors.initials: CB
authors.lastname: Cooley
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, United States.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Paxman
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, United States.
authors.forename: Ciara M
authors.initials: CM
authors.lastname: Gallagher
authors.affiliation: The Scripps Research Institute Molecular Screening Center, Translational Research Institute, Jupiter, United States.|Lead Identification Division, Translational Research Institute, Jupiter, United States.
authors.forename: Franck
authors.initials: F
authors.lastname: Madoux
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Genereux
authors.affiliation: Proteostasis Therapeutics Inc, Cambridge, United States.
authors.forename: Wesley
authors.initials: W
authors.lastname: Dobbs
authors.affiliation: Proteostasis Therapeutics Inc, Cambridge, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Garza
authors.affiliation: The Scripps Research Institute Molecular Screening Center, Translational Research Institute, Jupiter, United States.|Lead Identification Division, Translational Research Institute, Jupiter, United States.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.affiliation: The Scripps Research Institute Molecular Screening Center, Translational Research Institute, Jupiter, United States.|Lead Identification Division, Translational Research Institute, Jupiter, United States.
authors.forename: Louis
authors.initials: L
authors.lastname: Scampavia
authors.affiliation: The Scripps Research Institute Molecular Screening Center, La Jolla, United States.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brown
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.|The Scripps Research Institute Molecular Screening Center, La Jolla, United States.|Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, United States.
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, United States.
authors.forename: Peter
authors.identifier: 0000-0002-6849-708X
authors.initials: P
authors.lastname: Walter
authors.affiliation: The Scripps Research Institute Molecular Screening Center, Translational Research Institute, Jupiter, United States.|Lead Identification Division, Translational Research Institute, Jupiter, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.|Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States.
authors.forename: R Luke
authors.identifier: 0000-0001-9287-6840
authors.initials: RL
authors.lastname: Wiseman
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D051702:Activating Transcription Factor 6 / Q000096:biosynthesis*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D066263:Protein Aggregation, Pathological / Q000517:prevention & control*; D000074702:Proteostasis / Q000187:drug effects*; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D051702:Activating Transcription Factor 6
keywords: HEK293 cells; HepG2 cells; biochemistry; cell biology; mouse embryonic fibroblasts; none; patient-derived plasma cells