Abstract：
Understanding cellular coordination remains a challenge despite knowledge of individual pathways. The RNA exosome, targeting a wide range of RNA substrates, is often downregulated in cellular senescence. Utilizing an auxin-inducible system, we observed that RNA exosome depletion in embryonic stem cells significantly affects the transcriptome and proteome, causing pluripotency loss and pre-senescence onset. Mechanistically, exosome depletion triggers acute nuclear RNA aggregation, disrupting nuclear RNA-protein equilibrium. This disturbance limits nuclear protein availability and hinders polymerase initiation and engagement, reducing gene transcription. Concurrently, it promptly disrupts nucleolar transcription, ribosomal processes, and nuclear exporting, resulting in a translational shutdown. Prolonged exosome depletion induces nuclear structural changes resembling senescent cells, including aberrant chromatin compaction, chromocenter disassembly, and intensified heterochromatic foci. These effects suggest that the dynamic turnover of nuclear RNA orchestrates crosstalk between essential processes to optimize cellular function. Disruptions in nuclear RNA homeostasis result in systemic functional decline, altering the cell state and promoting senescence.
摘要：
尽管了解个体途径，但理解细胞协调仍然是一个挑战。RNA外泌体，靶向广泛的RNA底物，在细胞衰老中经常下调。利用生长素诱导系统，我们观察到胚胎干细胞中的RNA外泌体耗竭显著影响转录组和蛋白质组，导致多能性丧失和衰老前期。机械上,外泌体耗竭引发急性核RNA聚集，破坏核RNA-蛋白质平衡。这种干扰限制了核蛋白的可用性，并阻碍了聚合酶的启动和参与，减少基因转录。同时,它会迅速破坏核仁转录，核糖体过程，核出口，导致平移关闭。延长的外泌体耗竭诱导类似衰老细胞的核结构变化，包括异常染色质压实，色心拆卸,和强化异色焦点。这些效应表明，核RNA的动态周转会协调基本过程之间的串扰以优化细胞功能。核RNA稳态的破坏导致系统功能下降，改变细胞状态并促进衰老。
