Izquierdo José M
Departamento de Biología Molecular and the Centro de Biología Molecular Severo Ochoa, C.S.I.C., Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain.
J Biol Chem. 2008 Jul 4;283(27):19077-84. doi: 10.1074/jbc.M800017200. Epub 2008 May 7.
Exclusion of exon 6 by alternative RNA splicing of the primary transcript of the apoptosis receptor Fas produces a soluble isoform that prevents programmed cell death. I report that antiapoptotic regulator Hu antigen R (HuR, ELAVL1), a member of the embryonic lethal, abnormal vision, Drosophila-like (ELAVL) family, promotes Fas exon 6 skipping by binding to an exonic splicing silencer. HuR inhibits the association of U2 small nuclear ribonucleoprotein (snRNP) auxiliary factor 65 kDa (U2AF65) with the upstream 3' splice site, without decreasing recognition of the downstream 5' splice site by U1 snRNP but by antagonizing the role of TIA-1 (T-cell intracellular antigen 1)/TIAR (TIA-1 related protein) on exon definition. Remarkably, U1 snRNP-mediated recognition of the 5' splice site is partially required for efficient U2AF65 inhibition. Further, the silencing capacity of HuR as splicing regulator resides in the RRM1 and hinge-RRM3 domains. Taken together, these results support a functional link between HuR as repressor of alternative Fas splicing and the molecular mechanisms modulating programmed cell death.
凋亡受体Fas初级转录本通过可变RNA剪接排除外显子6，产生一种可防止程序性细胞死亡的可溶性异构体。我报告称，抗凋亡调节因子Hu抗原R（HuR，ELAVL1）是胚胎致死、异常视觉、果蝇样（ELAVL）家族的成员，它通过与外显子剪接沉默子结合促进Fas外显子6跳跃。HuR抑制U2小核核糖核蛋白（snRNP）辅助因子65 kDa（U2AF65）与上游3'剪接位点的结合，在不降低U1 snRNP对下游5'剪接位点识别的情况下，通过拮抗TIA-1（T细胞细胞内抗原1）/TIAR（TIA-1相关蛋白）在外显子定义上的作用。值得注意的是，高效抑制U2AF65部分需要U1 snRNP介导的对5'剪接位点的识别。此外，HuR作为剪接调节因子的沉默能力存在于RRM1和铰链-RRM3结构域中。综上所述，这些结果支持了HuR作为Fas可变剪接的抑制因子与调节程序性细胞死亡的分子机制之间的功能联系。
