CCT complex restricts neuropathogenic protein aggregation via autophagy
| Autor: | Pavel, M, Imarisio, S, Menzies, FM, Jimenez-Sanchez, M, Siddiqi, FH, Wu, X, Renna, M, O'Kane, CJ, Crowther, DC, Rubinsztein, DC |
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| Přispěvatelé: | Pavel, Mariana, Imarisio, Sara, Menzies, Fiona M., Jimenez-Sanchez, Maria, Siddiqi, Farah H., Wu, Xiaoting, Renna, Maurizio, O'Kane, Cahir J., Crowther, Damian C., Rubinsztein, David C., Siddiqi, Farah [0000-0001-9185-0163], O'Kane, Cahir [0000-0002-3488-2078], Rubinsztein, David [0000-0001-5002-5263], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
Huntingtin Protein Biochemistry Genetics and Molecular Biology (all) Science Chemistry (all) Autophagosomes RNA-Binding Proteins Mice Transgenic Protein Aggregation Pathological Physics and Astronomy (all) Autophagy Animals Humans Drosophila Female Ataxin-3 Lysosomes Chaperonin Containing TCP-1 HeLa Cells |
| Zdroj: | Nature Communications, Vol 7, Iss 1, Pp 1-18 (2016) |
| ISSN: | 2041-1723 |
| Popis: | Aberrant protein aggregation is controlled by various chaperones, including CCT (chaperonin containing TCP-1)/TCP-1/TRiC. Mutated CCT4/5 subunits cause sensory neuropathy and CCT5 expression is decreased in Alzheimer's disease. Here, we show that CCT integrity is essential for autophagosome degradation in cells or Drosophila and this phenomenon is orchestrated by the actin cytoskeleton. When autophagic flux is reduced by compromise of individual CCT subunits, various disease-relevant autophagy substrates accumulate and aggregate. The aggregation of proteins like mutant huntingtin, ATXN3 or p62 after CCT2/5/7 depletion is predominantly autophagy dependent, and does not further increase with CCT knockdown in autophagy-defective cells/organisms, implying surprisingly that the effect of loss-of-CCT activity on mutant ATXN3 or huntingtin oligomerization/aggregation is primarily a consequence of autophagy inhibition rather than loss of physiological anti-aggregation activity for these proteins. Thus, our findings reveal an essential partnership between two key components of the proteostasis network and implicate autophagy defects in diseases with compromised CCT complex activity. |
| Databáze: | OpenAIRE |
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