title: Small-molecule proteostasis regulators for protein conformational diseases.
abstract: Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting this mechanism as a promising therapeutic approach. We describe the results of a screen comprised of ∼900,000 small molecules that identified new classes of small-molecule proteostasis regulators that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. These beneficial effects to proteome stability are mediated by HSF-1, FOXO, Nrf-2 and the chaperone machinery through mechanisms that are distinct from current known small-molecule activators of the heat shock response. We suggest that modulation of the proteostasis network by proteostasis regulators may be a promising therapeutic approach for the treatment of a variety of protein conformational diseases.
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Calamini
authors.forename: Maria Catarina
authors.initials: MC
authors.lastname: Silva
authors.forename: Franck
authors.initials: F
authors.lastname: Madoux
authors.forename: Darren M
authors.initials: DM
authors.lastname: Hutt
authors.forename: Shilpi
authors.initials: S
authors.lastname: Khanna
authors.forename: Monica A
authors.initials: MA
authors.lastname: Chalfant
authors.forename: S Adrian
authors.initials: SA
authors.lastname: Saldanha
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Tait
authors.forename: Dan
authors.initials: D
authors.lastname: Garza
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D051858:Forkhead Transcription Factors / Q000187:drug effects; D000076249:Heat Shock Transcription Factors; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D018832:Molecular Chaperones / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D057165:Proteostasis Deficiencies / Q000188:drug therapy*; D051381:Rats; D014157:Transcription Factors / Q000187:drug effects*
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D018832:Molecular Chaperones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011506:Proteins; D014157:Transcription Factors