Evasion of the innate immune response: The Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II
Autor(es): Akhrymuk Ivan, Kulemzin Sergey V, Frolova Elena I
Resumo: 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, - Europe. The Old World alphaviruses are highly cytopathic - 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, - 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 - S-adenosylmethionine (SAM)-dependent methyltransferase-like domains, - 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, - 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 - 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.
Imprenta: Journal of Virology, v. 86, n. 13, p. 7180-7191, 2012
Identificador do objeto digital: 10.1128/JVI.00541-12
Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Immune response ; Chikungunya virus - Molecular structure ; Chikungunya virus - Protein synthesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya virus - Immune response ; Chikungunya Virus - Virus ; Chikungunya virus - Epidemic
Data de publicação: 2012
