Proteostatic Control of Telomerase Function through TRiC-Mediated Folding of TCAB1

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. [Display omitted] •Telomere maintenance requires assembly and trafficking of telomerase•Proteostasis factor TRiC folds the telomerase cofactor TCAB1•Loss of TRiC causes telomerase mislocalization and telomere elongation failure•TCAB1 mutations in patients disrupt TRiC-mediated folding, leading to disease The assembly and localization of telomerase and the consequent control of telomere elongation are found to be dependent upon the chaperonin TRiC. Mutations in the telomerase cofactor TCAB1 that impair its folding by TRiC cause dyskeratosis congenita, thus highlighting a proteostatic level of control of telomere function.