Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers.
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.
Behrends
Christian
C
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried.
Langer
Carola A
CA
Boteva
Raina
R
Böttcher
Ulrike M
UM
Stemp
Markus J
MJ
Schaffar
Gregor
G
Rao
Bharathi Vasudeva
BV
Giese
Armin
A
Kretzschmar
Hans
H
Siegers
Katja
K
Hartl
F Ulrich
FU
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
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