KIS counteracts PTBP2 and regulates alternative exon usage in neurons
KIS counteracts PTBP2 and regulates alternative exon usage in neurons
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DOI：
10.1101/2023.05.15.540804
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发表时间：
2023-05
期刊：
影响因子：
7.7
通讯作者：
Marcos Moreno-Aguilera;Mònica B. Mendoza;Alba M. Neher;Martin Dodel;F. Mardakheh;Raúl Ortiz;C. Gallego-C
中科院分区：
文献类型：
--
作者：
Marcos Moreno-Aguilera;Mònica B. Mendoza;Alba M. Neher;Martin Dodel;F. Mardakheh;Raúl Ortiz;C. Gallego-C
RNA选择性剪接是控制神经元分化和突触成熟的重要动态过程，该过程的失调与神经退行性疾病有关。最近的研究揭示了 RNA 结合蛋白在神经元剪接程序调节中的重要性。然而，控制这些剪接调节因子的分子机制仍不清楚。在这里，我们展示了 KIS（一种大脑富集激酶，其具有剪接因子共享的结构域）在全基因组水平上控制分化神经元中外显子的使用。 KIS 磷酸化剪接调节因子 PTBP2 复合物并显着抵消其外显子排除作用。在分子水平上，PTBP2 内非结构化结构域的磷酸化导致其与关键协同调节因子解离，并阻碍其 RNA 结合能力。总而言之，我们的数据为剪接调节因子的翻译后控制提供了新的见解，并揭示了 KIS 在设置神经元中替代外显子使用方面的重要作用。
Alternative RNA splicing is an essential and dynamic process to control neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here we show that KIS, a brain-enriched kinase with a domain shared by splicing factors, controls exon usage in differentiated neurons at a genome-wide level. KIS phosphorylates the splicing regulator PTBP2 complex and markedly counteracts its role in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from key co-regulators and hinders its RNA-binding capacity. Taken together, our data provide new insights into the post-translational control of splicing regulators and uncover an essential role of KIS in setting alternative exon usage in neurons.