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The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions

Nature Cell Biology volume 8, pages 1155–1162 (2006)Cite this article

Abstract

Misfolding and aggregation of proteins containing expanded polyglutamine repeats underlie Huntington's disease and other neurodegenerative disorders1. 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 biogenesis2, 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.

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Figure 1: Impaired TRiC function increases PolyQ-expanded huntingtin aggregation in budding yeast.
Figure 2: TRiC physically interacts with and directly suppresses aggregation of PolyQ-expanded huntingtin.
Figure 3: Specific TRiC subunits directly modulate PolyQ-expanded huntingtin aggregate morphology.
Figure 4: Impaired TRiC function increases PolyQ-expanded huntingtin aggregation in mammalian cells.
Figure 5: TRiC modulates aggregation of PolyQ-expanded huntingtin and alleviates cytotoxicity in neurons.

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Acknowledgements

We thank W. Zachariae, R. Kopito, R. Davis, N. Nukina and F. Sherman for kindly providing reagents and cells, P. Ren, V. Albanese, B. Riley, A.J. McClellan and other members of the Frydman and Kopito labs for advice and stimulating discussions and R. Andino for useful discussions and comments on the manuscript. This work was supported by National Institutes of Health (NIH) grants GM56433 and GM74074.

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  1. Biophysics Graduate Program, Stanford University, Stanford, 94305, California, USA

    Stephen Tam

  2. Department of Biological Sciences, Stanford University, Stanford, 94305, California, USA

    Stephen Tam, Ron Geller, Christoph Spiess & Judith Frydman

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  2. Ron Geller
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Contributions

S.T. and J.F. planned the project. S.T., R.G. and C.S. prepared reagents and performed experiments. S.T., R.G., C.S. and J.F. designed experiments, interpreted data and wrote the manuscript.

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Correspondence to Judith Frydman.

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The authors declare no competing financial interests.

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Supplementary figures S1, S2, S3, S4, S5 and Supplementary table S1. (PDF 312 kb)

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Tam, S., Geller, R., Spiess, C. et al. The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions. Nat Cell Biol 8, 1155–1162 (2006). https://doi.org/10.1038/ncb1477

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