Precise regulation of RNA metabolism is crucial for dynamic gene expression and controlling cellular functions. In the nervous system, defects in RNA metabolism are implicated in the disturbance of brain homeostasis and development. Here, we report that deubiquitinating enzyme, ubiquitin specific peptidase 15 (USP15), deubiquitinates terminal uridylyl transferase 1 (TUT1) and changes global RNA metabolism. We found that the expression of USP15 redistributes TUT1 from the nucleolus to nucleoplasm, resulting in the stabilization of U6 snRNA. We also found that lack of the Usp15 gene induces an impairment in motor ability with an unconventional cerebellar formation. Moreover, inhibition of the USP15-TUT1 cascade triggered mild and chronic endoplasmic reticulum (ER) stress. Therefore, our results suggest that USP15 is crucial for mRNA metabolism and maintains a healthy brain. These findings provide a possibility that disturbance of the USP15-TUT1 cascade induces chronic and mild ER stress, leading to an acceleration of the neurodegenerative phenotype.

中文翻译：

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USP15使与RNA代谢相关的TUT1去泛素化，并维持小脑稳态。

RNA代谢的精确调节对于动态基因表达和控制细胞功能至关重要。在神经系统中，RNA代谢的缺陷与脑稳态和发育的紊乱有关。在这里，我们报告去泛素化酶，泛素特异性肽酶15（USP15），去泛素化末端尿嘧啶转移酶1（TUT1），并改变全球RNA代谢。我们发现USP15的表达将TUT1从核仁重新分布到核质，导致U6 snRNA的稳定。我们还发现缺少Usp15基因诱导运动能力受损，形成非常规的小脑。此外，USP15-TUT1级联的抑制引发轻度和慢性内质网（ER）压力。因此，我们的结果表明，USP15对mRNA代谢至关重要，并能维持大脑健康。这些发现提供了一种可能性，即USP15-TUT1级联的紊乱会引起慢性和轻度的内质网应激，从而导致神经变性表型加速。