Rialdi Alexander, Hultquist Judd, Jimenez-Morales David, Peralta Zuleyma, Campisi Laura, Fenouil Romain, Moshkina Natasha, Wang Zhen Zhen, Laffleur Brice, Kaake Robyn M, McGregor Michael J, Haas Kelsey, Pefanis Evangelos, Albrecht Randy A, Pache Lars, Chanda Sumit, Jen Joanna, Ochando Jordi, Byun Minji, Basu Uttiya, García-Sastre Adolfo, Krogan Nevan, van Bakel Harm, Marazzi Ivan
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
Cell. 2017 May 4;169(4):679-692.e14. doi: 10.1016/j.cell.2017.04.021.
The nuclear RNA exosome is an essential multi-subunit complex that controls RNA homeostasis. Congenital mutations in RNA exosome genes are associated with neurodegenerative diseases. Little is known about the role of the RNA exosome in the cellular response to pathogens. Here, using NGS and human and mouse genetics, we show that influenza A virus (IAV) ribogenesis and growth are suppressed by impaired RNA exosome activity. Mechanistically, the nuclear RNA exosome coordinates the initial steps of viral transcription with RNAPII at host promoters. The viral polymerase complex co-opts the nuclear RNA exosome complex and cellular RNAs en route to 3' end degradation. Exosome deficiency uncouples chromatin targeting of the viral polymerase complex and the formation of cellular:viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs. Our results suggest that evolutionary arms races have shaped the cellular RNA quality control machinery.
核RNA外切体是一种控制RNA稳态的重要多亚基复合物。RNA外切体基因的先天性突变与神经退行性疾病有关。关于RNA外切体在细胞对病原体反应中的作用知之甚少。在这里，我们使用二代测序（NGS）以及人和小鼠遗传学方法表明，甲型流感病毒（IAV）的核糖核蛋白生成和生长受到RNA外切体活性受损的抑制。从机制上讲，核RNA外切体在宿主启动子处与RNA聚合酶II（RNAPII）协调病毒转录的初始步骤。病毒聚合酶复合物在通往3'端降解的途中利用核RNA外切体复合物和细胞RNA。外切体缺陷会使病毒聚合酶复合物的染色质靶向与细胞：病毒RNA杂交体的形成脱钩，而这些杂交体是许可反义基因组病毒RNA转录的必需RNA中间体。我们的结果表明，进化军备竞赛塑造了细胞RNA质量控制机制。
