Abstract
ABSTRACTInfluenza viruses subvert the transcriptional machinery of their hosts to synthesize their own viral mRNA. Ongoing transcription by cellular RNA polymerase II (Pol II) is required for viral mRNA synthesis. By a process known as cap snatching, the virus steals short 5′ capped RNA fragments from host capped RNAs and uses them to prime viral transcription. An interaction between the influenza A virus RNA polymerase and the C-terminal domain (CTD) of the large subunit of Pol II has been established, but the molecular details of this interaction remain unknown. We show here that the influenza virus ribonucleoprotein (vRNP) complex binds to the CTD of transcriptionally engaged Pol II. Furthermore, we provide evidence that the viral polymerase binds directly to the serine-5-phosphorylated form of the Pol II CTD, both in the presence and in the absence of viral RNA, and show that this interaction is conserved in evolutionarily distant influenza viruses. We propose a model in which direct binding of the viral RNA polymerase in the context of vRNPs to Pol II early in infection facilitates cap snatching, while we suggest that binding of free viral polymerase to Pol II late in infection may trigger Pol II degradation.IMPORTANCE Influenza viruses cause yearly epidemics and occasional pandemics that pose a threat to human health, as well as represent a large economic burden to health care systems globally. Existing vaccines are not always effective, as they may not exactly match the circulating viruses. Furthermore, there are a limited number of antivirals available, and development of resistance to these is a concern. New measures to combat influenza are needed, but before they can be developed, it is necessary to better understand the molecular interactions between influenza viruses and their host cells. By providing further insights into the molecular details of how influenza viruses hijack the host transcriptional machinery, we aim to uncover novel targets for the development of antivirals.
Highlights
Influenza viruses subvert the transcriptional machinery of their hosts to synthesize their own viral mRNA
The viral polymerase in the absence of NP and viral RNA (vRNA) has been shown to interact with polymerase II (Pol II) [11], it is unclear whether polymerase in the context of virus ribonucleoprotein (vRNP) can associate with Pol II
We investigated the molecular details of how the influenza virus transcriptional machinery interacts with cellular Pol II
Summary
Influenza viruses subvert the transcriptional machinery of their hosts to synthesize their own viral mRNA. An interaction between the influenza A virus RNA polymerase and the C-terminal domain (CTD) of the large subunit of Pol II has been established, but the molecular details of this interaction remain unknown. Despite the clear functional and physical links between the viral and host transcriptional machineries, the details of this interaction remain poorly understood It is not clear whether only free polymerase interacts with the CTD of Pol II or whether viral polymerase in the context of vRNPs can interact. The influenza virus polymerase requires active Pol II to provide it with a source of capped RNA primers, the viral polymerase has been linked to Pol II degradation This occurs at late times during infection [17, 18], when free polymerase is present, and coincides with the shutdown of viral mRNA synthesis [18]. Our results indicate that the viral polymerase can interact with the CTD of Pol II that is engaged in active transcription in RNA-free form, as well as in the context of vRNPs, raising the possibility that the interaction of the viral polymerase with Pol II could fulfill multiple functions
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