Kucherenko Mariya M, Shcherbata Halyna R
Max Planck Research Group of Gene Expression and Signaling, Max Planck Institute for Biophysical Chemistry, Am Fassberg, 11, Goettingen, 37077, Germany.
Nat Commun. 2018 Jan 22;9(1):312. doi: 10.1038/s41467-017-02757-w.
Upon stress, profound post-transcriptional adjustments of gene expression occur in spatially restricted, subcellular, membraneless compartments, or ribonucleoprotein (RNP) granules, which are formed by liquid phase separation of RNA-binding proteins with low complexity sequence domains (LCDs). Here, we show that Rbfox1 is an LCD-containing protein that aggregates into liquid droplets and amyloid-like fibers and promiscuously joins different nuclear and cytoplasmic RNP granules. Using Drosophila oogenesis as an in vivo system for stress response, we demonstrate a mechanism by which Rbfox1 promotes cell survival. The stress-dependent miRNA miR-980 acts to buffer Rbfox1 levels, since it targets only those Rbfox1 transcripts that contain extended 3'UTRs. Reduced miR-980 expression during stress leads to increased Rbfox1 levels, widespread formation of various RNP granules, and increased cell viability. We show that human RBFOX proteins also contain multiple LCDs and form membraneless compartments, suggesting that the RNP granule-linked control of cellular adaptive responses may contribute to a wide range of RBFOX-associated pathologies in humans.
在应激状态下，基因表达会在空间受限的亚细胞无膜区室或核糖核蛋白（RNP）颗粒中发生深刻的转录后调节，这些颗粒由具有低复杂性序列结构域（LCD）的RNA结合蛋白通过液相分离形成。在此，我们表明Rbfox1是一种含LCD的蛋白，它会聚集形成液滴和淀粉样纤维，并随机加入不同的核和细胞质RNP颗粒。利用果蝇卵子发生作为应激反应的体内系统，我们证明了Rbfox1促进细胞存活的机制。应激依赖性miRNA miR-980起到缓冲Rbfox1水平的作用，因为它仅靶向那些含有延长3'UTR的Rbfox1转录本。应激期间miR-980表达降低会导致Rbfox1水平升高、各种RNP颗粒广泛形成以及细胞活力增加。我们表明人类RBFOX蛋白也含有多个LCD并形成无膜区室，这表明RNP颗粒相关的细胞适应性反应控制可能导致人类多种与RBFOX相关的病理状况。
