Younis Ihab, Dittmar Kimberly, Wang Wei, Foley Shawn W, Berg Michael G, Hu Karen Y, Wei Zhi, Wan Lili, Dreyfuss Gideon
Department of Biochemistry and Biophysics , Howard Hughes Medical Institute, University of Pennsylvania School of Medicine , Philadelphia , United States.
Elife. 2013 Jul 30;2:e00780. doi: 10.7554/eLife.00780.
Eukaryotes have two types of spliceosomes, comprised of either major (U1, U2, U4, U5, U6) or minor (U11, U12, U4atac, U6atac; <1%) snRNPs. The high conservation of minor introns, typically one amidst many major introns in several hundred genes, despite their poor splicing, has been a long-standing enigma. Here, we discovered that the low abundance minor spliceosome's catalytic snRNP, U6atac, is strikingly unstable (t½<2 hr). We show that U6atac level depends on both RNA polymerases II and III and can be rapidly increased by cell stress-activated kinase p38MAPK, which stabilizes it, enhancing mRNA expression of hundreds of minor intron-containing genes that are otherwise suppressed by limiting U6atac. Furthermore, p38MAPK-dependent U6atac modulation can control minor intron-containing tumor suppressor PTEN expression and cytokine production. We propose that minor introns are embedded molecular switches regulated by U6atac abundance, providing a novel post-transcriptional gene expression mechanism and a rationale for the minor spliceosome's evolutionary conservation. DOI:http://dx.doi.org/10.7554/eLife.00780.001.
真核生物有两种剪接体，由主要（U1、U2、U4、U5、U6）或次要（U11、U12、U4atac、U6atac；<1%）小核核糖核蛋白（snRNP）组成。尽管次要内含子剪接效率低下，但在数百个基因中，通常在众多主要内含子中有一个次要内含子高度保守，这一直是个长期未解之谜。在此，我们发现低丰度次要剪接体的催化性小核核糖核蛋白U6atac极其不稳定（半衰期<2小时）。我们表明，U6atac水平依赖于RNA聚合酶II和III，细胞应激激活激酶p38丝裂原活化蛋白激酶（p38MAPK）可使其迅速增加，该激酶使其稳定，增强数百个含次要内含子基因的mRNA表达，否则这些基因会因U6atac受限而受到抑制。此外，p38MAPK依赖的U6atac调节可控制含次要内含子的肿瘤抑制因子PTEN的表达和细胞因子的产生。我们提出，次要内含子是受U6atac丰度调节的嵌入式分子开关，提供了一种新的转录后基因表达机制以及次要剪接体进化保守性的理论依据。DOI:http://dx.doi.org/10.7554/eLife.00780.001
