Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
College of Biological Sciences, School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Mol Cell Biol. 2020 Oct 13;40(21). doi: 10.1128/MCB.00098-20.
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 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.
精确调控 RNA 代谢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 代谢缺陷与脑内环境平衡和发育紊乱有关。在这里，我们报告去泛素化酶，泛素特异性肽酶 15（USP15），可使末端尿嘧啶核苷转移酶 1（TUT1）去泛素化，并改变全局 RNA 代谢。我们发现 USP15 的表达将 TUT1 从核仁重新分配到核质，导致 U6 snRNA 的稳定。我们还发现缺乏基因会导致运动能力受损，出现非传统的小脑形成。此外，抑制 USP15-TUT1 级联反应会引发轻度和慢性内质网（ER）应激。因此，我们的研究结果表明 USP15 对 mRNA 代谢至关重要，并维持大脑健康。这些发现为 USP15-TUT1 级联反应紊乱引发慢性和轻度内质网应激，导致神经退行性表型加速提供了可能性。
