Abstract
ABSTRACTThe influenza A virus genome consists of eight segments of single-stranded RNA. These segments are replicated and transcribed by a viral RNA-dependent RNA polymerase (RdRp) that is made up of the influenza virus proteins PB1, PB2, and PA. To copy the viral RNA (vRNA) genome segments and the cRNA segments, the replicative intermediate of viral replication, the RdRp must use two promoters and two different de novo initiation mechanisms. On the vRNA promoter, the RdRp initiates on the 3′ terminus, while on the cRNA promoter, the RdRp initiates internally and subsequently realigns the nascent vRNA product to ensure that the template is copied in full. In particular, the latter process, which is also used by other RNA viruses, is not understood. Here we provide mechanistic insight into priming and realignment during influenza virus replication and show that it is controlled by the priming loop and a helix-loop-helix motif of the PB1 subunit of the RdRp. Overall, these observations advance our understanding of how the influenza A virus initiates viral replication and amplifies the genome correctly.IMPORTANCE Influenza A viruses cause severe disease in humans and are considered a major threat to our economy and health. The viruses replicate and transcribe their genome by using an enzyme called the RNA polymerases. To ensure that the genome is amplified faithfully and that abundant viral mRNAs are made for viral protein synthesis, the RNA polymerase must work correctly. In this report, we provide insight into the mechanism that the RNA polymerase employs to ensure that the viral genome is copied correctly.
Highlights
The influenza A virus genome consists of eight segments of singlestranded RNA
Priming and realignment are essential for viral RNA synthesis
We previously showed that the initiation activities of the Influenza A viruses (IAVs) RNA-dependent RNA polymerase (RdRp) on these two promoters are similar during viral replication [13]
Summary
The influenza A virus genome consists of eight segments of singlestranded RNA. These segments are replicated and transcribed by a viral RNA-dependent RNA polymerase (RdRp) that is made up of the influenza virus proteins PB1, PB2, and PA. The latter molecules are exported from the nucleus and translated by cellular ribosomes, while cRNAs are bound by new NP and RdRp molecules in order to form cRNPs capable of synthesizing new vRNAs [3] Both IAV replication and transcription are catalyzed by the RdRp [1, 2]. Oymans and te Velthuis [5,6,7], while the remaining parts of PA and PB2 form flexible domains at the periphery of the polymerase core (Fig. 1A) These domains are important for cleaving cellular host mRNAs, a process that yields capped RNA primers that are essential for viral transcription [1, 4]
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