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Review
. 2011 Mar-Apr;8(2):207-15.
doi: 10.4161/rna.8.2.14513. Epub 2011 Mar 1.

The influenza virus RNA synthesis machine: advances in its structure and function

Patricia Resa-Infante  1 , Núria Jorba, Rocio Coloma, Juan Ortin
Affiliations
Review

The influenza virus RNA synthesis machine: advances in its structure and function

Patricia Resa-Infante et al. RNA Biol. 2011 Mar-Apr.

Abstract

The influenza A viruses are the causative agents of respiratory disease that occurs as yearly epidemics and occasional pandemics. These viruses are endemic in wild avian species and can sometimes break the species barrier to infect and generate new virus lineages in humans. The influenza A virus genome consists of eight single-stranded, negative-polarity RNAs that form ribonucleoprotein complexes by association to the RNA polymerase and the nucleoprotein. In this review we focus on the structure of this RNA-synthesis machines and the included RNA polymerase, and on the mechanisms by which they express their genetic information as mRNAs and generate progeny ribonucleoproteins that will become incorporated into new infectious virions. New structural, biochemical and genetic data are rapidly accumulating in this very active area of research. We discuss these results and attempt to integrate the information into structural and functional models that may help the design of new experiments and further our knowledge on virus RNA replication and gene expression. This interplay between structural and functional data will eventually provide new targets for controlled attenuation or antiviral therapy.

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Figures

Figure 1
Figure 1
Structure of an influenza virus ribonucleoprotein complex. (A) A perspective view and two side views of the three-dimensional structure of a recombinant RNP; (B) A top view of the same structure with the atomic structure of the NP docked (pdb 2IQH) into each monomer; (C) A front view of the polymerase complex present in the recombinant RNP with a proposed docking of the atomic structure of the PA(C)-PB1(N) domain (pdb 2ZNL).
Figure 2
Figure 2
Diagram of intersubunit interactions in the influenza polymerase complex. The diagram represents the polymerase subunits as bars in which the N- and C-terminal regions are indicated. The domains of each subunit whose atomic structure has been determined are indicated by underlined regions and the corresponding structures are presented (PA: Yellow; PB1: Blue; PB2: Green). The interaction domains identified biochemically that have been verified by co-crystallisation are indicated by boxes connected by dotted lines. Relevant functional domains (Endonuclease, RdRp and cap-binding domains) are also highlighted.
Figure 3
Figure 3
Structural comparison of RNP-associated and soluble polymerase complexes. Several views are presented to compare the structures of the soluble heterotrimer devoid of template RNA (top, pink), the polymerase complex present in the recombinant RNP (middle, yellow), and a polymerase-vRNA complex (bottom, blue).
Figure 4
Figure 4
Structural and mechanistic differences between influenza virus transcription and replication processes. The diagram shows the structure of a helical vRNP (middle), including the negative-polarity template RNA (red) associated to NP monomers (orange circles). The polymerase subunits are coloured in blue (PB1), green (PB2) and yellow (PA). The promoter is depicted in its corkscrew structure and the location of the polyadenylation signal (oligo U) is indicated. The structure of the mRNA product of transcription is presented at the bottom, including the capped oligonucleotide primer (boxed in green) and the poly A tail. The structure of the cRNP intermediate of replication in presented at the top, including the positive-polarity template RNA (blue) and the promoter elements.
Figure 5
Figure 5
A trans model for the second step in influenza RNA replication. The diagram presents the proposed process for generation of progeny vRNPs. (A) cRNP template; (B) A non-resident polymerase complex (NRP1, -semitransparent-) would access the 3′-end of the template and initiate de novo. As the vRNA product is produced, a second nonresident polymerase (NRP2, -semitransparent-) would recognise and protect the 5′-terminus, inducing the association of NP. Oligomerisation of additional NP monomers would continue protection and encapsidation of the vRNA product. Subsequent initiation events by additional NRP1 complexes could increase the replication efficiency on the same template; (C) Progression of the replication complexes formed by NRP1 would eventually displace the resident polymerase (opaque) from the 5′-terminus of the cRNA template, thus allowing complete replication; (D) Structure of the progeny vRNP.
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