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Novel roles of the picornaviral 3D polymerase in viral pathogenesis.

ABSTRACT: The RNA-dependent RNA-polymerase, 3D(pol), is an essential component in the picornavirus genome for the replication of single stranded RNA. However, transgenic expression of 3D(pol) in mice has antiviral effects. Here we discuss the structure and function of 3D(pol) during picornavirus replication, we review the evidence and consequence of a host immune response to epitopes in 3D(pol) after picornavirus infection, highlight data showing the antiviral effects of transgenic 3D(pol) from Theiler's murine encephalomyelitis virus (TMEV), and discuss potential mechanisms by which 3D(pol) is causing this antiviral effect in mice.

SUBMITTER: Kerkvliet J

PROVIDER: S-EPMC2897181 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Novel roles of the picornaviral 3D polymerase in viral pathogenesis.

Kerkvliet Jason J Edukulla Ramakrishna R Rodriguez Moses M

Advances in virology 20100101

The RNA-dependent RNA-polymerase, 3D(pol), is an essential component in the picornavirus genome for the replication of single stranded RNA. However, transgenic expression of 3D(pol) in mice has antiviral effects. Here we discuss the structure and function of 3D(pol) during picornavirus replication, we review the evidence and consequence of a host immune response to epitopes in 3D(pol) after picornavirus infection, highlight data showing the antiviral effects of transgenic 3D(pol) from Theiler's ...[more]

PMID: 20625447

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Project description:Accumulating evidence suggests that viruses hijack cellular proteins to circumvent the host immune system. Ubiquitination and SUMOylation are extensively studied posttranslational modifications (PTMs) that play critical roles in diverse biological processes. Cross talk between ubiquitination and SUMOylation of both host and viral proteins has been reported to result in distinct functional consequences. Enterovirus 71 (EV71), an RNA virus belonging to the family Picornaviridae, is a common cause of hand, foot, and mouth disease. Little is known concerning how host PTM systems interact with enteroviruses. Here, we demonstrate that the 3D protein, an RNA-dependent RNA polymerase (RdRp) of EV71, is modified by small ubiquitin-like modifier 1 (SUMO-1) both during infection and in vitro Residues K159 and L150/D151/L152 were responsible for 3D SUMOylation as determined by bioinformatics prediction combined with site-directed mutagenesis. Also, primer-dependent polymerase assays indicated that mutation of SUMOylation sites impaired 3D polymerase activity and virus replication. Moreover, 3D is ubiquitinated in a SUMO-dependent manner, and SUMOylation is crucial for 3D stability, which may be due to the interplay between the two PTMs. Importantly, increasing the level of SUMO-1 in EV71-infected cells augmented the SUMOylation and ubiquitination levels of 3D, leading to enhanced replication of EV71. These results together suggested that SUMO and ubiquitin cooperatively regulated EV71 infection, either by SUMO-ubiquitin hybrid chains or by ubiquitin conjugating to the exposed lysine residue through SUMOylation. Our study provides new insight into how a virus utilizes cellular pathways to facilitate its replication.ImportanceInfection with enterovirus 71 (EV71) often causes neurological diseases in children, and EV71 is responsible for the majority of fatalities. Based on a better understanding of interplay between virus and host cell, antiviral drugs against enteroviruses may be developed. As a dynamic cellular process of posttranslational modification, SUMOylation regulates global cellular protein localization, interaction, stability, and enzymatic activity. However, little is known concerning how SUMOylation directly influences virus replication by targeting viral polymerase. Here, we found that EV71 polymerase 3D was SUMOylated during EV71 infection and in vitro Moreover, the SUMOylation sites were determined, and in vitro polymerase assays indicated that mutations at SUMOylation sites could impair polymerase synthesis. Importantly, 3D is ubiquitinated in a SUMOylation-dependent manner that enhances the stability of the viral polymerase. Our findings indicate that the two modifications likely cooperatively enhance virus replication. Our study may offer a new therapeutic strategy against virus replication.

Dataset Information

Novel roles of the picornaviral 3D polymerase in viral pathogenesis.

Publications

Novel roles of the picornaviral 3D polymerase in viral pathogenesis.

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