title: A genetic screening strategy identifies novel regulators of the proteostasis network.
abstract: A hallmark of diseases of protein conformation and aging is the appearance of protein aggregates associated with cellular toxicity. We posit that the functional properties of the proteostasis network (PN) protect the proteome from misfolding and combat the proteotoxic events leading to cellular pathology. In this study, we have identified new components of the proteostasis network that can suppress aggregation and proteotoxicity, by performing RNA interference (RNAi) genetic screens for multiple unrelated conformationally challenged cytoplasmic proteins expressed in Caenorhabditis elegans. We identified 88 suppressors of polyglutamine (polyQ) aggregation, of which 63 modifiers also suppressed aggregation of mutant SOD1(G93A). Of these, only 23 gene-modifiers suppressed aggregation and restored animal motility, revealing that aggregation and toxicity can be genetically uncoupled. Nine of these modifiers were shown to be effective in restoring the folding and function of multiple endogenous temperature-sensitive (TS) mutant proteins, of which five improved folding in a HSF-1-dependent manner, by inducing cytoplasmic chaperones. This triage screening strategy also identified a novel set of PN regulatory components that, by altering metabolic and RNA processing functions, establish alternate cellular environments not generally dependent on stress response activation and that are broadly protective against misfolded and aggregation-prone proteins.
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: M Catarina
authors.initials: MC
authors.lastname: Silva
authors.forename: Susan
authors.initials: S
authors.lastname: Fox
authors.forename: Monica
authors.initials: M
authors.lastname: Beam
authors.forename: Happy
authors.initials: H
authors.lastname: Thakkar
authors.forename: Margarida D
authors.initials: MD
authors.lastname: Amaral
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D005820:Genetic Testing / Q000379:methods*; D018869:Heat-Shock Response / Q000235:genetics; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D057165:Proteostasis Deficiencies; D034622:RNA Interference; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; D010455:Peptides; C000606290:SOD1 protein, human; D014157:Transcription Factors; C474710:heat shock factor-1, C elegans; C097188:polyglutamine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1