Journal Article

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

Huang, Peng-Nien, Cameron, Craig E., Liu, Yen-Chin, Kuo, Rei-Lin, Arnold, Jamine J., Shih, Shin-Ru, Wang, Robert Yung-Liang, Lin, Jing-Yi, Liu, Hsuan, Huang, Yi, Chen, Shu-Jen

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Biology and Life Sciences / Care and treatment / Cell Line / Cell Nucleus - metabolism / Cell Nucleus - virology / Cytoplasm / Cytoplasm - enzymology / Cytoplasm - metabolism / Cytoplasm - virology / Diagnosis / Distribution / Enterovirus - metabolism / Enterovirus - pathogenicity / Enterovirus A, Human - metabolism / Enterovirus A, Human - pathogenicity / Fingers & toes / Gene expression / Genomes / Health aspects / Humans / Libraries / Machinery / Medicine and Health Sciences / Nuclear Localization Signals / Pathogenesis / Poliovirus - metabolism / Poliovirus - pathogenicity / Proteases / Protein Biosynthesis / Protein Interaction Domains and Motifs / Proteins / Recombinant Proteins - chemistry / Recombinant Proteins - metabolism / Rhinovirus - metabolism / Rhinovirus - pathogenicity / RNA / RNA polymerase / RNA Precursors - antagonists & inhibitors / RNA Precursors - metabolism / RNA Splicing / RNA, Messenger - antagonists & inhibitors / RNA, Messenger - metabolism / RNA-Binding Proteins - antagonists & inhibitors / RNA-Binding Proteins - chemistry / RNA-Binding Proteins - metabolism / RNA-Directed DNA Polymerase - chemistry / RNA-Directed DNA Polymerase - genetics / RNA-Directed DNA Polymerase - metabolism / Species Specificity / Transcription, Genetic / Viral infections / Viral Load / Viral Proteins - chemistry / Viral Proteins - genetics / Viral Proteins - metabolism / Virulence / Virus diseases / Viruses