A genetic screening strategy identifies novel regulators of the proteostasis network.

  • Silva M
  • Fox S
  • Beam M
 et al. 
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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.

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Authors

  • M Silva

  • Susan Fox

  • Monica Beam

  • Happy Thakkar

  • Margarida Amaral

  • Richard Morimoto

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