Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state.
Polyglutamine (polyQ)-expansion proteins cause neurodegenerative disorders including Huntington's disease, Kennedy's disease and various ataxias. The cytotoxicity of these proteins is associated with the formation of aggregates or other conformationally toxic species. Here, we show that the cytosolic chaperonin CCT (also known as TRiC) can alter the course of aggregation and cytotoxicity of huntingtin (Htt)-polyQ proteins in mammalian cells. Disruption of the CCT complex by RNAi-mediated knockdown enhanced Htt-polyQ aggregate formation and cellular toxicity. Analysis of the aggregation states of the Htt-polyQ proteins by fluorescence correlation spectroscopy revealed that CCT depletion results in the appearance of soluble Htt-polyQ aggregates. Similarly, overexpression of all eight subunits of CCT suppressed Htt aggregation and neuronal cell death. These results indicate that CCT has an essential role in protecting against the cytotoxicity of polyQ proteins by affecting the course of aggregation.
Kitamura
Akira
A
Department of Molecular and Cellular Biology and CREST/JST, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8397, Japan.
Kubota
Hiroshi
H
Pack
Chan-Gi
CG
Matsumoto
Gen
G
Hirayama
Shoshiro
S
Takahashi
Yasuo
Y
Kimura
Hiroshi
H
Kinjo
Masataka
M
Morimoto
Richard I
RI
Nagata
Kazuhiro
K
D000818:Animals; D002478:Cells, Cultured; D056404:Chaperonin Containing TCP-1; 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 / Q000633:toxicity*; D011485:Protein Binding
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C533315:Tcp1 protein, mouse; C097188:polyglutamine; D056404:Chaperonin Containing TCP-1; D018833:Chaperonins