RRC ID 47314
著者 Pavel M, Imarisio S, Menzies FM, Jimenez-Sanchez M, Siddiqi FH, Wu X, Renna M, O'Kane CJ, Crowther DC, Rubinsztein DC.
タイトル CCT complex restricts neuropathogenic protein aggregation via autophagy.
ジャーナル Nat Commun
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.
巻・号 7
ページ 13821
公開日 2016-12-8
DOI 10.1038/ncomms13821
PII ncomms13821
PMID 27929117
PMC PMC5155164
MeSH Animals Ataxin-3 / metabolism Autophagosomes / metabolism* Autophagy* Chaperonin Containing TCP-1 / metabolism* Drosophila Female HeLa Cells Humans Huntingtin Protein / metabolism* Lysosomes / metabolism Male Mice, Transgenic Protein Aggregation, Pathological / metabolism* RNA-Binding Proteins / metabolism
IF 12.121
引用数 43
WOS 分野 CELL BIOLOGY
リソース情報
ショウジョウバエ 8439R-1 8439R-4