Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1

Adam Freund; Franklin L. Zhong; Andrew S. Venteicher; Zhaojing Meng; Timothy D. Veenstra; Judith Frydman; Steven E. Artandi

doi:10.1016/j.cell.2014.10.059

Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1

Adam Freund, Franklin L. Zhong, Andrew S. Venteicher, Zhaojing Meng, Timothy D. Veenstra, Judith Frydman, Steven E. Artandi

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1389-1403
Number of pages	15
Journal	Cell
Volume	159
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2014.10.059
State	Published - Dec 4 2014
Externally published	Yes

Bibliographical note

Funding Information:
We thank members of the Artandi and Frydman labs for helpful discussions and advice. We thank David Solow-Cordero in the Stanford High-Throughput Bioscience Center, with support from NIH NCRR Instrumentation grant S10RR026338. We are grateful to Anthony Tomlinson for generously providing purified bovine TRiC and to Sharon Savage for supplying DC patient lymphoblasts. A.F. was supported by Stanford Cancer Biology Training Program (T32 CA09302) and by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. F.L.Z. was supported by a fellowship from the Agency for Science, Technology, and Research (A ∗ STAR), Singapore. This work was supported by NIH grants AG033747, CA125453, CA111691, and AG036695 and by the Glenn Foundation for Medical Research.

Publisher Copyright:
© 2014 Elsevier Inc.

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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.",

author = "Adam Freund and Zhong, {Franklin L.} and Venteicher, {Andrew S.} and Zhaojing Meng and Veenstra, {Timothy D.} and Judith Frydman and Artandi, {Steven E.}",

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PY - 2014/12/4

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N2 - 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.

AB - 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.

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Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1

Abstract

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