title: Cytoplasmic viral RNA-dependent RNA polymerase disrupts the intracellular splicing machinery by entering the nucleus and interfering with Prp8.
abstract: 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.
authors: 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.
authors: Yen-Chin
authors: YC
authors: Liu
authors: 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.
authors: Rei-Lin
authors: RL
authors: Kuo
authors: School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan.
authors: Jing-Yi
authors: JY
authors: Lin
authors: Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors: Peng-Nien
authors: PN
authors: Huang
authors: Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan.
authors: Yi
authors: Y
authors: Huang
authors: Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan.
authors: Hsuan
authors: H
authors: Liu
authors: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors: Jamine J
authors: JJ
authors: Arnold
authors: Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan.
authors: Shu-Jen
authors: SJ
authors: Chen
authors: Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Biomedical Sciences and Graduate Institutes of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors: Robert Yung-Liang
authors: RY
authors: Wang
authors: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors: Craig E
authors: CE
authors: Cameron
authors: 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; Clinical Virology Laboratory, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors: Shin-Ru
authors: SR
authors: Shih
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism* / Q000821:virology; D003593:Cytoplasm / Q000201:enzymology* / Q000378:metabolism / Q000821:virology; D004770:Enterovirus / Q000378:metabolism / Q000472:pathogenicity; D029821:Enterovirus A, Human / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D019913:Nuclear Localization Signals; D017955:Poliovirus / Q000378:metabolism / Q000472:pathogenicity; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D012322:RNA Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012229:Rhinovirus / Q000378:metabolism / Q000472:pathogenicity; D013045:Species Specificity; D014158:Transcription, Genetic; D019562:Viral Load; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: D019913:Nuclear Localization Signals; C115374:PRPF8 protein, human; D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D014764:Viral Proteins; D012194:RNA-Directed DNA Polymerase