title: Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers.
abstract: Aberrant folding and fibrillar aggregation by polyglutamine (polyQ) expansion proteins are associated with cytotoxicity in Huntington's disease and other neurodegenerative disorders. Hsp70 chaperones have an inhibitory effect on fibril formation and can alleviate polyQ cytotoxicity. Here we show that the cytosolic chaperonin, TRiC, functions synergistically with Hsp70 in this process and is limiting in suppressing polyQ toxicity in a yeast model. In vitro reconstitution experiments revealed that TRiC, in cooperation with the Hsp70 system, promotes the assembly of polyQ-expanded fragments of huntingtin (Htt) into soluble oligomers of approximately 500 kDa. Similar oligomers were observed in yeast cells upon TRiC overexpression and were found to be benign, in contrast to conformationally distinct Htt oligomers of approximately 200 kDa, which accumulated at normal TRiC levels and correlated with inhibition of cell growth. We suggest that TRiC cooperates with the Hsp70 system as a key component in the cellular defense against amyloid-like protein misfolding.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried.
authors.forename: Christian
authors.initials: C
authors.lastname: Behrends
authors.forename: Carola A
authors.initials: CA
authors.lastname: Langer
authors.forename: Raina
authors.initials: R
authors.lastname: Boteva
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Böttcher
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Stemp
authors.forename: Gregor
authors.initials: G
authors.lastname: Schaffar
authors.forename: Bharathi Vasudeva
authors.initials: BV
authors.lastname: Rao
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Katja
authors.initials: K
authors.lastname: Siegers
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Hartl
mesh_terms: D018833:Chaperonins / Q000378:metabolism / Q000502:physiology*; D042622:DNA Repeat Expansion; D049452:Green Fluorescent Proteins / Q000032:analysis; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000032:analysis; D020449:Repetitive Sequences, Amino Acid; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D018833:Chaperonins