Project description:Circular RNAs (circRNAs) accumulate with age, but their functional impact on aging remains elusive. In this study, we reveal a mechanism by which ribonuclease κ (RNASEK) prevents age-dependent circRNA accumulation by promoting its degradation. Through a genetic screen targeting ribonucleases, we identified RNASEK as a specific circRNA-cleaving ribonuclease. RNASEK is downregulated during aging, causing the age-dependent increase in circRNA levels. RNASEK is necessary and sufficient for lifespan extension and healthspan maintenance in Caenorhabditis elegans. Mammalian RNASEK also directly degrades circRNAs, and is required for preventing premature aging in cultured human cells and mice, indicating its evolutionarily conserved role. Notably, we demonstrate that circRNAs localize within stress granules, where RNASEK, in collaboration with HSP90, prevents toxic aggregation of circRNAs in aged organisms. Our study establishes RNASEK as a conserved regulator of aging and offers a framework for targeting circRNAs to mitigate age-associated diseases and to extend organismal healthspan.
Project description:Circular RNAs (circRNAs) accumulate with age, but their functional impact on aging remains elusive. In this study, we reveal a mechanism by which ribonuclease κ (RNASEK) prevents age-dependent circRNA accumulation by promoting its degradation. Through a genetic screen targeting ribonucleases, we identified RNASEK as a specific circRNA-cleaving ribonuclease. RNASEK is downregulated during aging, causing the age-dependent increase in circRNA levels. RNASEK is necessary and sufficient for lifespan extension and healthspan maintenance in Caenorhabditis elegans. Mammalian RNASEK also directly degrades circRNAs, and is required for preventing premature aging in cultured human cells and mice, indicating its evolutionarily conserved role. Notably, we demonstrate that circRNAs localize within stress granules, where RNASEK, in collaboration with HSP90, prevents toxic aggregation of circRNAs in aged organisms. Our study establishes RNASEK as a conserved regulator of aging and offers a framework for targeting circRNAs to mitigate age-associated diseases and to extend organismal healthspan.
Project description:Circular RNAs (circRNAs) accumulate with age, but their functional impact on aging remains elusive. In this study, we reveal a mechanism by which ribonuclease κ (RNASEK) prevents age-dependent circRNA accumulation by promoting its degradation. Through a genetic screen targeting ribonucleases, we identified RNASEK as a specific circRNA-cleaving ribonuclease. RNASEK is downregulated during aging, causing the age-dependent increase in circRNA levels. RNASEK is necessary and sufficient for lifespan extension and healthspan maintenance in Caenorhabditis elegans. Mammalian RNASEK also directly degrades circRNAs, and is required for preventing premature aging in cultured human cells and mice, indicating its evolutionarily conserved role. Notably, we demonstrate that circRNAs localize within stress granules, where RNASEK, in collaboration with HSP90, prevents toxic aggregation of circRNAs in aged organisms. Our study establishes RNASEK as a conserved regulator of aging and offers a framework for targeting circRNAs to mitigate age-associated diseases and to extend organismal healthspan.
Project description:Circular RNAs (circRNAs) are vital in many physiological and pathological events. Compared to the other processes of circRNA metabolism, circRNA degradation is less understood. Through screening and further characterization, RNAseK and lysosome are identified as circRNA degradation modules in metazoan, and RNase 1 as a lysosomal circRNA endoribonuclease in mammal. RNAseK and lysosome function synergistically with RNAseK degrading circRNAs outside and lysosome degrading those inside of the organelle. Mutations of RNAseK- or lysosome-sensitive sites in in vitro synthesized circRNA reporters lead to higher expression levels, and simultaneous mutations of both sensitive sites result in further increase. Under stress stimuli such as heat shock and ER stress, significantly decreased global circRNA levels are observed in C. elegans. RNAseK deficiency or lysosome inhibition diminishes the decreases in circRNA levels, and impedes the induction of stress response, suggesting that circRNA degradation by RNAseK and lysosome plays protective roles in C. elegans stress response.
