CCT complex restricts neuropathogenic protein aggregation via autophagy

Mariana Pavel, Sara Imarisio, Fiona M. Menzies, Maria Jimenez-Sanchez, Farah H. Siddiqi, Xiaoting Wu, Maurizio Renna, Cahir J. O’Kane, Damian C. Crowther and David C. Rubinsztein ()
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Mariana Pavel: University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital
Sara Imarisio: University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital
Fiona M. Menzies: University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital
Maria Jimenez-Sanchez: University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital
Farah H. Siddiqi: University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital
Xiaoting Wu: University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital
Maurizio Renna: University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital
Cahir J. O’Kane: University of Cambridge
Damian C. Crowther: University of Cambridge
David C. Rubinsztein: University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13821

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