Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan

Nat Commun. 2016 Nov 28:7:13649. doi: 10.1038/ncomms13649.

Abstract

Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington's disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / physiology*
  • Cell Differentiation
  • Chaperonin Containing TCP-1 / metabolism*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Longevity*
  • Mutation / genetics
  • Phenotype
  • Pluripotent Stem Cells / metabolism*
  • Protein Aggregates
  • Protein Subunits / metabolism
  • Proteostasis*
  • Stress, Physiological

Substances

  • Protein Aggregates
  • Protein Subunits
  • CCT8 protein, human
  • Chaperonin Containing TCP-1