title: Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1.
abstract: Telomere maintenance by telomerase is impaired in the stem cell disease dyskeratosis congenita and during human aging. Telomerase depends upon a complex pathway for enzyme assembly, localization in Cajal bodies, and association with telomeres. Here, we identify the chaperonin CCT/TRiC as a critical regulator of telomerase trafficking using a high-content genome-wide siRNA screen in human cells for factors required for Cajal body localization. We find that TRiC is required for folding the telomerase cofactor TCAB1, which controls trafficking of telomerase and small Cajal body RNAs (scaRNAs). Depletion of TRiC causes loss of TCAB1 protein, mislocalization of telomerase and scaRNAs to nucleoli, and failure of telomere elongation. DC patient-derived mutations in TCAB1 impair folding by TRiC, disrupting telomerase function and leading to severe disease. Our findings establish a critical role for TRiC-mediated protein folding in the telomerase pathway and link proteostasis, telomere maintenance, and human disease.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Freund
authors.affiliation: Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Franklin L
authors.initials: FL
authors.lastname: Zhong
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Venteicher
authors.affiliation: Laboratory of Proteomics and Analytical Technologies, Science Applications International Corporation-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Laboratory of Proteomics and Analytical Technologies, Science Applications International Corporation-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: sartandi@stanford.edu.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Artandi
mesh_terms: D056404:Chaperonin Containing TCP-1 / Q000378:metabolism*; D019871:Dyskeratosis Congenita / Q000235:genetics / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018832:Molecular Chaperones; D017510:Protein Folding; D019098:Telomerase / Q000737:chemistry / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D019098:Telomerase; C535133:WRAP53 protein, human; D056404:Chaperonin Containing TCP-1