Nova autoregulation reveals dual functions in neuronal splicing
Nova autoregulation reveals dual functions in neuronal splicing
复制标题
DOI：
10.1038/sj.emboj.7600630
复制
发表时间：
2005-04-20
期刊：
影响因子：
11.4
通讯作者：
Darnell, RB
中科院分区：
文献类型：
--
作者：
Dredge, BK;Stefani, G;Darnell, RB
Nova家族的神经元特异性RNA结合蛋白最初被确定为一种以运动抑制失败为特征的自身免疫性神经疾病的靶标。Nova-1通过直接结合内含子元件，调节编码抑制性神经递质受体亚单位GABA(A)R Gamma 2和GlyR Alpha 2的前mRNAs的选择性剪接，导致外显子包含性增强。在这里，我们确定了Nova-1前-mRNA本身中的外显子E4，编码一个磷酸化的蛋白结构域，作为依赖Nova的小鼠脊髓剪接调控的额外靶点。NovA与E4的结合是NovA依赖外显子排除的必要条件和充分条件。E4含有已知的NovA结合四核苷酸YCAY的五个重复，这些元件的突变破坏了NovA依赖的调控。此外，从Nova-1和GABA(A)R Gamma 2的位点交换表明，Nova增强或抑制替代外显子包含的能力取决于NovA结合元件在Pre-mRNA中的位置。这些研究表明，除了先前所描述的剪接激活因子之外，Nova还通过作为剪接抑制因子来自动调节自己的表达。
The Nova family of neuron-specific RNA-binding proteins were originally identified as targets in an autoimmune neurologic disease characterized by failure of motor inhibition. Nova-1 regulates alternative splicing of pre-mRNAs encoding the inhibitory neurotransmitter receptor subunits GABA(A)R gamma 2 and GlyR alpha 2 by directly binding intronic elements, resulting in enhancement of exon inclusion. Here we identify exon E4 in the Nova-1 pre-mRNA itself, encoding a phosphorylated protein domain, as an additional target of Nova-dependent splicing regulation in the mouse spinal cord. Nova binding to E4 is necessary and sufficient for Nova-dependent exon exclusion. E4 harbors five repeats of the known Nova-binding tetra-nucleotide YCAY and mutation of these elements destroys Nova-dependent regulation. Furthermore, swapping of the sites from Nova-1 and GABA(A)R gamma 2 indicates that the ability of Nova to enhance or repress alternative exon inclusion is dependent on the position of the Nova-binding element within the pre-mRNA. These studies demonstrate that in addition to its previously described role as a splicing activator, Nova autoregulates its own expression by acting as a splicing repressor.