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2024-3-29 4:59:57


Walker AP, Sharps J, Fodor E. Mutation of an influenza virus polymerase 3´ RNA promoter binding site inhibits transcription elongation. J Virol. 2020 Apr 15. pii: JVI.00498-20.
submited by kickingbird at Apr, 18, 2020 14:7 PM from J Virol. 2020 Apr 15. pii: JVI.00498-20.

Influenza A virus encodes a viral RNA-dependent RNA polymerase (FluPolA), which is responsible for transcribing and replicating the negative-sense viral RNA (vRNA) genome. FluPolA transcribes vRNA using a host capped mRNA primer, and replicates it by synthesising a positive-sense complementary RNA (cRNA) intermediate which is copied back into vRNA. To carry out these functions, FluPolA interacts with vRNA and cRNA using conserved promoter elements at the 5´ and 3´ termini. Recent structural studies have identified a new surface binding site for the 3´ vRNA and cRNA promoters on FluPolA, referred to as the Mode B site. However, the role of this binding site in FluPolA function is unknown. In this study we used a combination of cell-based and biochemical assays to show that the Mode B site is important for both viral genome transcription and replication. Furthermore, we show that the Mode B site is not needed for initiating transcription in vitro but is required to synthesise a full-length product. This is consistent with a model in which the 3´ terminus of the vRNA template binds in the Mode B site during elongation. Our data provide the first functional insights into the role of the Mode B site on FluPolA, which advances our understanding of FluPolA function and influenza A virus replication.IMPORTANCE Influenza viruses are responsible for up to 650000 deaths per year through seasonal epidemics, and pandemics have caused tens of millions of deaths in the past. Most current therapeutics suffer from widespread resistance, creating a need for new drug targets against influenza virus. The virus encodes an RNA-dependent RNA polymerase, which replicates and transcribes the vRNA genome. The polymerase interacts with vRNA and the complementary replicative intermediate cRNA using several specific binding sites, however, the functions associated with these binding sites remain unknown. Here, we functionally characterise a binding site for the 3´ vRNA and cRNA promoters. Our data offer insight into the mechanism of viral genome transcription by the influenza virus polymerase, and may be applicable to other related viruses.

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