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  • CCT complex restricts neuropathogenic protein aggregation via autophagy.

CCT complex restricts neuropathogenic protein aggregation via autophagy.

Nature communications (2016-12-09)
Mariana Pavel, Sara Imarisio, Fiona M Menzies, Maria Jimenez-Sanchez, Farah H Siddiqi, Xiaoting Wu, Maurizio Renna, Cahir J O'Kane, Damian C Crowther, David C Rubinsztein
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, 1 mg/mL, clone M2, affinity isolated antibody, buffered aqueous solution (50% glycerol, 10 mM sodium phosphate, and 150 mM NaCl, pH 7.4)
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Monoclonal Anti-CCT5 antibody produced in mouse, clone 4E5-4B1, purified immunoglobulin, buffered aqueous solution
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Anti-Polyglutamines antibody, Mouse monoclonal, ~2 mg/mL, clone 3B5H10, purified from hybridoma cell culture
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Monoclonal Anti-α-Tubulin antibody produced in mouse, clone DM1A, ascites fluid
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Anti-CCT7 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution