Departments of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, 422 Curie Blvd, Philadelphia, PA, 19104, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., Box 1124, New York, NY, 10029, USA.
Nat Commun. 2018 Jun 19;9(1):2407. doi: 10.1038/s41467-018-04779-4.
Three of the eight RNA segments encoded by the influenza A virus (IAV) undergo alternative splicing to generate distinct proteins. Previously, we found that host proteins hnRNP K and NS1-BP regulate IAV M segment splicing, but the mechanistic details were unknown. Here we show NS1-BP and hnRNP K bind M mRNA downstream of the M2 5' splice site (5'ss). NS1-BP binds most proximal to the 5'ss, partially overlapping the U1 snRNP binding site, while hnRNP K binds further downstream and promotes U1 snRNP recruitment. Mutation of either or both the hnRNP K and NS1-BP-binding sites results in M segment mis-splicing and attenuated IAV replication. Additionally, we show that hnRNP K and NS1-BP regulate host splicing events and that viral infection causes mis-splicing of some of these transcripts. Therefore, our proposed mechanism of hnRNP K/NS1-BP mediated IAV M splicing provides potential targets of antiviral intervention and reveals novel host functions for these proteins.
流感 A 病毒（IAV）的 8 个 RNA 片段中有 3 个通过选择性剪接生成不同的蛋白质。此前，我们发现宿主蛋白 hnRNP K 和 NS1-BP 调节 IAV M 片段剪接，但具体机制尚不清楚。在这里，我们发现 NS1-BP 和 hnRNP K 结合在 M2 5' 剪接位点（5'ss）下游的 M mRNA 上。NS1-BP 结合在离 5'ss 最近的位置，部分与 U1 snRNP 结合位点重叠，而 hnRNP K 结合在更远的下游位置，并促进 U1 snRNP 的募集。hnRNP K 和 NS1-BP 结合位点的突变导致 M 片段剪接错误和 IAV 复制减弱。此外，我们还表明 hnRNP K 和 NS1-BP 调节宿主剪接事件，并且病毒感染导致其中一些转录物的剪接错误。因此，我们提出的 hnRNP K/NS1-BP 介导的 IAV M 剪接机制为抗病毒干预提供了潜在的靶点，并揭示了这些蛋白质的新的宿主功能。
Zotero 插件
