Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA
Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA
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DOI：
10.1038/nchembio.2007.18
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发表时间：
2007-09-01
影响因子：
14.8
通讯作者：
Yoshida, Minoru
中科院分区：
文献类型：
--
作者：
Kaida, Daisuke;Motoyoshi, Hajime;Yoshida, Minoru
剪接体催化转录物中插入序列的去除，剪接体是一种在新合成的前 mRNA 上组装的多组分复合物。细胞质中的前 mRNA 翻译会导致产生潜在有害的异常蛋白质。因此，严格控制以防止不需要的前 mRNA 从细胞核输出及其随后的翻译是可靠基因表达的基本要求。在此，我们证明天然产物 FR901464 (1) 及其甲基化衍生物 spliceostatin A (2) 可通过与剪接体中 U2 小核核糖核蛋白的亚复合物 SF3b 结合来抑制体外剪接并促进前 mRNA 积累。重要的是，用这些化合物处理细胞会导致前 mRNA 渗漏到细胞质中，并在细胞质中进行翻译。小干扰 RNA 敲低 SF3b 诱导的表型与剪接抑素 A 治疗相似。因此，在涉及 SF3b 的早期步骤中抑制前 mRNA 剪接会导致未剪接的 mRNA 泄漏和翻译。
The removal of intervening sequences from transcripts is catalyzed by the spliceosome, a multicomponent complex that assembles on the newly synthesized pre-mRNA. Pre-mRNA translation in the cytoplasm leads to the generation of aberrant proteins that are potentially harmful. Therefore, tight control to prevent undesired pre-mRNA export from the nucleus and its subsequent translation is an essential requirement for reliable gene expression. Here, we show that the natural product FR901464 (1) and its methylated derivative, spliceostatin A (2), inhibit in vitro splicing and promote pre-mRNA accumulation by binding to SF3b, a subcomplex of the U2 small nuclear ribonucleoprotein in the spliceosome. Importantly, treatment of cells with these compounds resulted in leakage of pre-mRNA to the cytoplasm, where it was translated. Knockdown of SF3b by small interfering RNA induced phenotypes similar to those seen with spliceostatin A treatment. Thus, the inhibition of pre-mRNA splicing during early steps involving SF3b allows unspliced mRNA leakage and translation.