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

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.

T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

“…CCT also binds to misfolded proteins and regulate their oligomerization/aggregation (1, 3, 4). Recent studies suggest that CCT exerts strong neuroprotective effects in Huntington’s disease (HD) (5–9). Expression of either a single or all eight subunits (CCT1–8) or application of the 20 kDa substrate-binding apical domain of yeast CCT1 (ApiCCT1) prevented aggregation of mutant Huntingtin (mHTT) protein, leading to improved cellular or neuronal functions (5–8, 10).…”

“…1,3,4 Recent studies suggest that CCT exerts strong neuroprotective effects in Huntington's disease (HD). [5][6][7][8][9] Expression of either a single or all eight subunits (CCT1-8) or application of the 20 kDa substrate-binding apical domain of yeast CCT1 (ApiCCT1) prevented aggregation of mutant Huntingtin (mHTT) protein, leading to improved cellular or neuronal functions. [5][6][7][8]10 In addition, CCT inhibited amyloid fiber assembly of α-synuclein mutant A53T, associated with Parkinson disease (PD), pointing out a similar neuroprotective role for CCT in PD.…”

A systematic atlas of chaperome deregulation topologies across the human cancer landscape

“…Given the "stemness" phenotype of cancer cells and their resemblances with pluripotent stem cells we hypothesized that the consistent chaperome upregulation in cancers acts to mimic an enhanced stem cell PN setup. Increased proteasome activity (Vilchez et al 2012) and elevated overall levels of the TRiC/CCT complex (Noormohammadi et al 2016), representatives of the clearance and folding functional arms of the PN, respectively, have recently been associated with the intrinsic PN of pluripotent stem cells that acts to support their identity and immortality. It can be hypothesized that increased levels of central PN processes in stem cells exemplify characteristics of an enhanced PN setup.…”

“…TRiC/CCT is highly conserved and essential for cell viability (Lopez et al 2015). Loss of complex subunits induces cell death and a decline of pluripotency of hESCs and induced pluripotent stem cells (iPSCs) (Noormohammadi et al 2016). Within the PN, TRiC/CCT mediated folding and autophagic clearance act in concert to prevent aggregation (Pavel et al 2016).…”

“…Within the PN, TRiC/CCT mediated folding and autophagic clearance act in concert to prevent aggregation (Pavel et al 2016). TRiC/CCT levels decline during stem cell differentiation, and CCT8 acts as complex assembly factor (Noormohammadi et al 2016). Intrigued by the finding that CCT8 is the most highly elevated subunit in stem cells and likely acting as TRiC/CCT assembly factor (Noormohammadi et al 2016), we assessed differential expression of individual TRiC/CCT subunits across cancers.…”