Cytoplasmic Viral RNA-Dependent RNA Polymerase Disrupts the Intracellular Splicing Machinery by Entering the Nucleus and Interfering with Prp8

PLoS Pathogens

Craig E. Cameron¹  Yi Huang²  Rei-Lin Kuo³  Peng-Nien Huang³  Shin-Ru Shih⁴  Shu-Jen Chen⁴  Robert Yung-Liang Wang⁴  Jamine J. Arnold⁵  Yen-Chin Liu⁵  Jing-Yi Lin⁵  Hsuan Liu⁶ 

[1] Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America;Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan;Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan;Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan;Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan;School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan

关键词: RNA splicing;    Messenger RNA;    Recombinant proteins;    Cytoplasm;    RNA sequencing;    Picornaviruses;    Polymerases;    Viral replication;   

DOI  :  10.1371/journal.ppat.1004199

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 (3Dpol) also enters the host nucleus, where its function remains unclear. In this study, we describe a novel mechanism of viral attack in which 3Dpol 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 3Dpol 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 Prp8-3Dpol 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.

【 授权许可】

CC BY