title: 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.
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Alireza
authors.initials: A
authors.lastname: Noormohammadi
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Amirabbas
authors.initials: A
authors.lastname: Khodakarami
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gutierrez-Garcia
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Seda
authors.initials: S
authors.lastname: Koyuncu
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: König
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schindler
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Saez
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: Azra
authors.initials: A
authors.lastname: Fatima
authors.affiliation: Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Computational Cardiology, Neuenheimer Feld 669, University Hospital, Heidelberg 69120, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dieterich
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
authors.forename: David
authors.identifier: 0000-0002-0801-0743
authors.initials: D
authors.lastname: Vilchez
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D002454:Cell Differentiation; D056404:Chaperonin Containing TCP-1 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008136:Longevity; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D066329:Protein Aggregates; D021122:Protein Subunits / Q000378:metabolism; D000074702:Proteostasis; D013312:Stress, Physiological
chemical_list: D066329:Protein Aggregates; D021122:Protein Subunits; C000610437:CCT8 protein, human; D056404:Chaperonin Containing TCP-1