Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing.
Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing.
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DOI：
10.1016/j.molcel.2010.09.013
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发表时间：
2010-10-08
期刊：
影响因子：
16
通讯作者：
Lynch KW
中科院分区：
文献类型：
--
作者：
Heyd F;Lynch KW
人T细胞中CD 45基因的信号诱导的选择性剪接对于适当的免疫功能至关重要。CD 45可变外显子的跳跃在很大程度上是由T细胞活化后PSF向前mRNA底物的募集控制的;然而，导致外显子排除的信号级联仍然是难以捉摸的。在这里，我们证明了在静息T细胞中，PSF被GSK 3直接磷酸化，从而促进PSF与TRAP 150的相互作用，TRAP 150阻止PSF结合CD 45前mRNA。在T细胞活化后，降低的GSK 3活性导致PSF磷酸化降低，从TRAP 150释放PSF并使其结合CD 45剪接调控元件并抑制外显子包含。我们的数据将两个新的参与者GSK 3和TRAP 150置于调节CD 45选择性剪接的复杂网络中，并展示了通过多功能蛋白PSF从细胞表面到RNA加工机制的信号转导的新范式。
Signal-induced alternative splicing of the CD45 gene in human T cells is essential for proper immune function. Skipping of the CD45 variable exons is controlled, in large part, by the recruitment of PSF to the pre-mRNA substrate upon T cell activation; however, the signaling cascade leading to exon exclusion has remained elusive. Here we demonstrate that in resting T cells PSF is directly phosphorylated by GSK3 thus promoting interaction of PSF with TRAP150 which prevents PSF from binding CD45 pre-mRNA. Upon T cell activation, reduced GSK3 activity leads to reduced PSF phosphorylation, releasing PSF from TRAP150 and allowing it to bind CD45 splicing regulatory elements and repress exon inclusion. Our data place two new players, GSK3 and TRAP150, in the complex network that regulates CD45 alternative splicing and demonstrate a new paradigm for signal transduction from the cell surface to the RNA processing machinery through the multi-functional protein PSF.
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