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.

中文翻译：

---

核RNA稳态促进细胞命运和衰老的系统级协调

尽管了解个体途径，但理解细胞协调仍然是一个挑战。 RNA 外泌体针对多种 RNA 底物，在细胞衰老过程中经常被下调。利用生长素诱导系统，我们观察到胚胎干细胞中RNA外泌体的消耗显着影响转录组和蛋白质组，导致多能性丧失和衰老前期的发生。从机制上讲，外泌体消耗会引发急性核 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聚合酶的启动和参与，从而减少基因转录。同时，它会迅速破坏核仁转录、核糖体过程和核输出，导致翻译关闭。长时间的外泌体消耗会诱导类似于衰老细胞的核结构变化，包括染色质压缩异常、染色中心分解和异染色质灶增强。这些效应表明，核 RNA 的动态周转协调了重要过程之间的串扰，以优化细胞功能。核 RNA 稳态的破坏会导致全身功能下降，改变细胞状态并促进衰老。