Evasion of the Innate Immune Response: the Old World Alphavirus nsP2 Protein Induces Rapid Degradation of Rpb1, a Catalytic Subunit of RNA Polymerase II
- 1 July 2012
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 86 (13), 7180-7191
- https://doi.org/10.1128/jvi.00541-12
Abstract
The Old World alphaviruses are emerging human pathogens with an ability to cause widespread epidemics. The latest epidemic of Chikungunya virus, from 2005 to 2007, affected over 40 countries in Africa, Asia, and Europe. The Old World alphaviruses are highly cytopathic and known to evade the cellular antiviral response by inducing global inhibition of transcription in vertebrate cells. This function was shown to be mediated by their nonstructural nsP2 protein; however, the detailed mechanism of this phenomenon has remained unknown. Here, we report that nsP2 proteins of Sindbis, Semliki Forest, and Chikungunya viruses inhibit cellular transcription by inducing rapid degradation of Rpb1, a catalytic subunit of the RNAPII complex. This degradation of Rpb1 is independent of the nsP2-associated protease activity, but, instead, it proceeds through nsP2-mediated Rpb1 ubiquitination. This function of nsP2 depends on the integrity of the helicase and S -adenosylmethionine (SAM)-dependent methyltransferase-like domains, and point mutations in either of these domains abolish Rpb1 degradation. We go on to show that complete degradation of Rpb1 in alphavirus-infected cells occurs within 6 h postinfection, before other previously described virus-induced changes in cell physiology, such as apoptosis, autophagy, and inhibition of STAT1 phosphorylation, are detected. Since Rpb1 is a subunit that catalyzes the polymerase reaction during RNA transcription, degradation of Rpb1 plays an indispensable role in blocking the activation of cellular genes and downregulating cellular antiviral response. This indicates that the nsP2-induced degradation of Rpb1 is a critical mechanism utilized by the Old World alphaviruses to subvert the cellular antiviral response.Keywords
This publication has 39 references indexed in Scilit:
- Interferon Antagonist NSs of La Crosse Virus Triggers a DNA Damage Response-like Degradation of Transcribing RNA Polymerase IIPublished by Elsevier BV ,2011
- Functional Sindbis Virus Replicative Complexes Are Formed at the Plasma MembraneJournal of Virology, 2010
- Venezuelan Equine Encephalitis Virus Capsid Protein Forms a Tetrameric Complex with CRM1 and Importin α/β That Obstructs Nuclear Pore Complex FunctionJournal of Virology, 2010
- Random Insertion Mutagenesis of Sindbis Virus Nonstructural Protein 2 and Selection of Variants Incapable of Downregulating Cellular TranscriptionJournal of Virology, 2009
- hnRNP A1 Interacts with the 5′ Untranslated Regions of Enterovirus 71 and Sindbis Virus RNA and Is Required for Viral ReplicationJournal of Virology, 2009
- Semliki Forest Virus Nonstructural Protein 2 Is Involved in Suppression of the Type I Interferon ResponseJournal of Virology, 2007
- The Old World and New World Alphaviruses Use Different Virus-Specific Proteins for Induction of Transcriptional ShutoffJournal of Virology, 2007
- Interaction of Bunyamwera Orthobunyavirus NSs Protein with Mediator Protein MED8: a Mechanism for Inhibiting the Interferon ResponseJournal of Virology, 2006
- Sindbis Virus Nonstructural Protein nsP2 Is Cytotoxic and Inhibits Cellular TranscriptionJournal of Virology, 2006
- Shuttling of pre-mRNA binding proteins between nucleus and cytoplasmNature, 1992