The role of the influenza virus RNA polymerase in host shut-off

Abstract

Viruses induce an antiviral host response by activating the expression of antiviral host genes. However, viruses have evolved a wide range of strategies to counteract antiviral host responses. One of the strategies used by many viruses is the general inhibition of host gene expression, also referred to as a host shut-off mechanism. Here we discuss our recent findings that influenza virus infection results in the inhibition and degradation of host RNA polymerase II (Pol II) and that the viral RNA polymerase plays a critical role in this process. In particular, we found that Pol II is ubiquitylated in influenza virus infected cells and ubiquitylation can be induced by the expression of the RNA polymerase. Moreover, the expression of an antiviral host gene could be inhibited by the over-expression of the RNA polymerase. Both ubiquitylation and the inhibition of the host gene were dependent on the ability of the RNA polymerase to bind to Pol II. Further studies will be required to understand the interplay between the host and viral transcriptional machineries and to elucidate the exact molecular mechanisms that lead to the inhibition and degradation of Pol II as a result of viral RNA polymerase binding. These findings extend our understanding of how influenza virus counteracts antiviral host responses and underpin studies into the mechanisms by which the RNA polymerase determines virulence.

Acknowledgements

Research in E.F.'s laboratory is supported by grants from the Medical Research Council and the Wellcome Trust.

Figures and Tables

Figure 1 Schematic model for the Pol II transcription cycle in cells infected with influenza virus and the role of the viral RNA polymerase in the inhibition and degradation of Pol II. The model depicts the large subunit of Pol II with the C-terminal domain (CTD) which is differentially phosphorylated during the transcription cycle (indicated by red and green dots). During the transcription cycle cellular factors involved in capping, splicing and polyadenylation associate with the CTD. The polyadenylation signal AATAAA is indicated. In influenza virus infected cells, the viral RNA polymerase (composed of the PB1, PB2 and PA subunits) binds to the serine-5 phosphorylated CTD of Pol II engaged in transcription initiation. On one hand, this association allows the viral RNA polymerase to access the 5′ cap structure of nascent Pol II transcripts and on the other, it results in the premature termination of Pol II. Arrested Pol II is ubiquitylated (Ub) by the cellular machinery and eventually is degraded by the proteasome. Modified from Chan et al.27

Addendum to: