title: The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions.
abstract: Misfolding and aggregation of proteins containing expanded polyglutamine repeats underlie Huntington's disease and other neurodegenerative disorders. Here, we show that the hetero-oligomeric chaperonin TRiC (also known as CCT) physically interacts with polyglutamine-expanded variants of huntingtin (Htt) and effectively inhibits their aggregation. Depletion of TRiC enhances polyglutamine aggregation in yeast and mammalian cells. Conversely, overexpression of a single TRiC subunit, CCT1, is sufficient to remodel Htt-aggregate morphology in vivo and in vitro, and reduces Htt-induced toxicity in neuronal cells. Because TRiC acts during de novo protein biogenesis, this chaperonin may have an early role preventing Htt access to pathogenic conformations. Based on the specificity of the Htt-CCT1 interaction, the CCT1 substrate-binding domain may provide a versatile scaffold for therapeutic inhibitors of neurodegenerative disease.
authors.affiliation: Biophysics Graduate Program, Stanford University, Stanford, California 94305, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tam
authors.forename: Ron
authors.initials: R
authors.lastname: Geller
authors.forename: Christoph
authors.initials: C
authors.lastname: Spiess
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018833:Chaperonins / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; C097188:polyglutamine; D018833:Chaperonins