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.
Highlights
Aberrant protein aggregation is controlled by various chaperones, including CCT/TCP-1/TRiC
A recent study observed that both CCT3 and the apical domain of CCT1 (ApiCCT1) reduced htt levels in cortical neurons from an Huntington’s disease mouse model, which was associated with normalized anterograde BDNF transport, restored retrograde BDNF transport and normalized lysosomal transport[14]
CCT depletion blocks autophagosome degradation in Drosophila. We further explored these phenomena in vivo using Drosophila, where we downregulated the CCT5 homologue, Cct[5], using two independent RNA interference (RNAi) lines (Cct5KK or Cct5NIG, whose sequences do not overlap) or the CCT7 homologue, Cct[7], using the Cct7KK RNAi line
Summary
Aberrant protein aggregation is controlled by various chaperones, including CCT (chaperonin containing TCP-1)/TCP-1/TRiC. Recent studies suggested that mRNA levels of the TRiC complex are repressed in Alzheimer’s disease patient brain samples[6] This might be important, as tau, which accumulates in Alzheimer’s disease, is a client protein of many chaperones and co-chaperones (Hsp90/CHIP and Hsp[70] complexes), including CCT, that together control both its stabilization and degradation[7]. We and others anticipated that the main role of this chaperone was to directly regulate the aggregation of huntingtin and related substrates While this direct binding/ sequestration mechanism represents an intuitive mechanism for CCT to regulate mutant huntingtin aggregation, indirect mechanisms dependent on degradation pathways have not been tested, or excluded previously. We report our unexpected findings that loss of CCT function increases the accumulation of well characterized aggregate-prone proteins, like the N-terminal mutant htt fragment, mainly as a consequence of autophagy inhibition
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