title: CCT complex restricts neuropathogenic protein aggregation via autophagy.
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.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Mariana
authors.initials: M
authors.lastname: Pavel
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Imarisio
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Jimenez-Sanchez
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Farah H
authors.initials: FH
authors.lastname: Siddiqi
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Renna
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Cahir J
authors.initials: CJ
authors.lastname: O'Kane
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.|MedImmune Limited, Aaron Klug Building, Granta Park, Cambridge CB21 6GH, UK.
authors.forename: Damian C
authors.initials: DC
authors.lastname: Crowther
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: David C
authors.identifier: 0000-0001-5002-5263
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D000067699:Ataxin-3 / Q000378:metabolism; D000071182:Autophagosomes / Q000378:metabolism*; D001343:Autophagy; D056404:Chaperonin Containing TCP-1 / Q000378:metabolism*; D004330:Drosophila; D005260:Female; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: D000071058:Huntingtin Protein; C118585:P62 protein, human; D016601:RNA-Binding Proteins; D000067699:Ataxin-3; D056404:Chaperonin Containing TCP-1