Liu Yen-Chin, Kuo Rei-Lin, Lin Jing-Yi, Huang Peng-Nien, Huang Yi, Liu Hsuan, Arnold Jamine J, Chen Shu-Jen, Wang Robert Yung-Liang, Cameron Craig E, Shih Shin-Ru
Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
PLoS Pathog. 2014 Jun 26;10(6):e1004199. doi: 10.1371/journal.ppat.1004199. eCollection 2014 Jun.
The primary role of cytoplasmic viral RNA-dependent RNA polymerase (RdRp) is viral genome replication in the cellular cytoplasm. However, picornaviral RdRp denoted 3D polymerase (3D(pol)) also enters the host nucleus, where its function remains unclear. In this study, we describe a novel mechanism of viral attack in which 3D(pol) enters the nucleus through the nuclear localization signal (NLS) and targets the pre-mRNA processing factor 8 (Prp8) to block pre-mRNA splicing and mRNA synthesis. The fingers domain of 3D(pol) associates with the C-terminal region of Prp8, which contains the Jab1/MPN domain, and interferes in the second catalytic step, resulting in the accumulation of the lariat form of the splicing intermediate. Endogenous pre-mRNAs trapped by the Prp8-3D(pol) complex in enterovirus-infected cells were identified and classed into groups associated with cell growth, proliferation, and differentiation. Our results suggest that picornaviral RdRp disrupts pre-mRNA splicing processes, that differs from viral protease shutting off cellular transcription and translation which contributes to the pathogenesis of viral infection.
细胞质病毒RNA依赖性RNA聚合酶（RdRp）的主要作用是在细胞质中进行病毒基因组复制。然而，小RNA病毒的RdRp即3D聚合酶（3D(pol)）也会进入宿主细胞核，其在细胞核中的功能尚不清楚。在本研究中，我们描述了一种新的病毒攻击机制，即3D(pol)通过核定位信号（NLS）进入细胞核，并靶向前体mRNA加工因子8（Prp8）以阻断前体mRNA剪接和mRNA合成。3D(pol)的指状结构域与Prp8的C末端区域结合，该区域包含Jab1/MPN结构域，并干扰第二步催化反应，导致套索状剪接中间体的积累。在肠道病毒感染的细胞中，鉴定出被Prp8-3D(pol)复合物捕获的内源性前体mRNA，并将其分类为与细胞生长、增殖和分化相关的组。我们的结果表明，小RNA病毒RdRp破坏前体mRNA剪接过程，这与病毒蛋白酶关闭细胞转录和翻译不同，后者有助于病毒感染的发病机制。
