Abstract
Influenza virus expresses transcripts early in infection and transitions towards genome replication at later time points. This process requires de novo assembly of the viral replication machinery, large ribonucleoprotein complexes (RNPs) composed of the viral polymerase, genomic RNA and oligomeric nucleoprotein (NP). Despite the central role of RNPs during infection, the factors dictating where and when they assemble are poorly understood. Here we demonstrate that human protein kinase C (PKC) family members regulate RNP assembly. Activated PKCδ interacts with the polymerase subunit PB2 and phospho-regulates NP oligomerization and RNP assembly during infection. Consistent with its role in regulating RNP assembly, knockout of PKCδ impairs virus infection by selectively disrupting genome replication. However, primary transcription from pre-formed RNPs deposited by infecting particles is unaffected. Thus, influenza virus exploits host PKCs to regulate RNP assembly, a step required for the transition from primary transcription to genome replication during the infectious cycle.
Highlights
Influenza virus infections initiate with a burst of gene expression from pre-formed ribonucleoprotein complexes (RNPs) deposited by the incoming viral particles
As NP oligomerization and RNP assembly are required for replication of the viral genome, we undertook a targeted approach to investigate the role of protein kinase C (PKC) in regulating influenza polymerase activity
We focused on PKCd given that NP exclusively interacts with full-length PKCd (Figure 2B,D), PKCd phospho-regulates NP oligomerization and RNP assembly (Figure 3), and that PKCd is abundantly expressed in human lung tissue, typical sites of influenza virus replication, and the human lung epithelial A549 cells used here (Goldberg and Steinberg, 1996)
Summary
Influenza virus infections initiate with a burst of gene expression from pre-formed RNPs deposited by the incoming viral particles. Primary transcription is followed by replication of the genome and subsequent transcription of the replicated genome, further increasing gene expression. This transition from transcription to replication requires the de novo assembly of RNPs and is absolutely required for successful infection and the production of infectious progeny.
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