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Front Biol    2011, Vol. 6 Issue (6) : 446-461    https://doi.org/10.1007/s11515-011-1151-5
REVIEW
Molecular mechanisms of transcription and replication of the influenza A virus genome
Shijian ZHANG1, Tetsuya TOYODA2,3()
1. Shanghai Medical College of Fudan University, Shanghai 200032, China; 2. Choju Medical Institute, Fukushimura Hospital, 19-14 Azanakayama, Noyori-cho, Toyohashi, Aichi 441-8124, Japan; 3. Infectious Disease Regulation Project, Tokyo Metropolitan Institute of Medical Sciences, 1-6, Kamikitazawa 2-chome, Setagaya-ku, Tokyo156-8506, Japan
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Abstract

Influenza A virus is one of the major pathogens that pose a large threat to human health worldwide and has caused pandemics. Influenza A virus is the Orthomyxoviridae prototype, and has 8 segmented negative-sense single-stranded RNA (vRNA) as its genome. Influenza virus RNA polymerase (RdRp) consists of three subunits PB2, PB1 and PA, and catalyzes both transcription and replication. Recently, intensive biochemical and structural analysis of its RdRp has been performed. In this paper, we review the details from the biochemical analysis of the purified influenza virus RdRp and the classical ribonucleoprotein complex, as well as piece together their structures to form an overall picture.
Keywords influenza virus      RNA polymerase      ribonucleoprotein complex      transcription      replication     
Corresponding Author(s): TOYODA Tetsuya,Email:toyoda_tetsuya@yahoo.co.jp   
Issue Date: 01 December 2011
 Cite this article:   
Shijian ZHANG,Tetsuya TOYODA. Molecular mechanisms of transcription and replication of the influenza A virus genome[J]. Front Biol, 2011, 6(6): 446-461.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-011-1151-5
https://academic.hep.com.cn/fib/EN/Y2011/V6/I6/446
Fig.1  Schematic diagram of influenza virus RNP. Schematic diagram (A) and cryoelectron micrograph of influenza virus RNP (B). Influenza virus RdRp, consisting of PA, PB1, and PB2 subunits, binds to the 3′-promoter/origin and 5′-end of vRNA. vRNA surrounds the NP homotrimer (see Fig. 5). The cryoelectron micrograph was modified from Fig. 6B of Area et al. ().
Fig.2  Schematic diagram of influenza virus transcription initiation and poly(A) tailing. A: Binding of PB1 subunit to the 5′-end of vRNA activates PB2 cap binding activity and PA endonuclease activity, which cleaves host cellular pre-mRNA to produce a 13-17 nucleotide long capped RNA primer. B: A guanosine residue is added to the capped RNA primer, initiating the viral transcription process. C: The vRNA template is read in the 3′ to 5′ direction. However, the 5′-end remains bound to the PB1 subunit. Therefore, RdRp begins to stutter-read upon encountering the U stretch, thus producing the poly(A) tail.
Fig.3  Schematic diagram of influenza virus replication initiation. Two steps of replication are carried out by different initiation mechanisms. A: vRNA → cRNA, host cellular terminal nucleotidyl transferases (TNT) add one nucleotide residue to the 3′-end of vRNA. Viral RdRp reads vRNA immediately after the addition of this extra nucleotide, thereby initiating cRNA replication. B: cRNA → vRNA, viral RdRp synthesizes pppApG directed by the 2nd UC sequence from the 3′-cRNA end. The pppApG motif realigns with the first UC from the 3′- cRNA end because of the instability of the pppApG-cRNA-protein complex. RdRp begins to elongate nascent RNA when the UTP concentration is high.
Fig.4  
Fig.5  The structure of influenza virus RNA polymerase. A: Schematic diagram of influenza virus RdRp. Functional domains, including nuclear localization signal (NLS), polymerase motif (Pol Motif), and nucleotide binding domain of PB1, are indicated. Ternary structures of RdRp solved are indicated in red. B: The PA (C)-PB1 (N) complex. PA (C) is indicated in cyan and PB1 (N) is indicated in green. The red part represents the PB1 LLFL motif. Alpha helices α10, α11, and α13 grasp PB1 (N), and beta sheets β8 and β9 wraps PB1 (N) PDB accession number: 2ZNL. C: The nuclease domain of PA. PDB accession number: 3EBJ. D: The PB2 (N)-PB1 (C) complex. The resolved complex structure was rotated to show the electrostatic interactions. Unlike the PA-PB1 complex, the interaction of which mainly depends on non-polar interactions, PB2 (N)-PB1 (C) predominantly interacts on the basis of electrostatic interactions. PDB accession number: 2ZTT. E: The cap binding domain of PB2. The sandwich structure is formed by the 5 phenylalanine residues and 1 histidine residue on either side with an m7GTP in between. PDB accession number: 2VQZ. F: Enhanced view of PB2 residue 627. (a) The electrostatic potential of PB2 3/3 was calculated using the GRASP program. Blue and red indicate basic and acidic surfaces, respectively. Basic regions (I) and (III) are separated by the loop (II). (b) The electrostatic potential of PB2 3/3 E627 was calculated using the GRASP program. Modified from Fig. 2 of Kuzuhara et al. (). G: PB2 C-terminal NLS. PDB accession number: 3L56. Figures were rendered in PyMOL (http://www.pymol.org/).
Fig.6  Charge distribution on the NP surface. Figures were rendered in PyMOL (PDB accession number 2IQH).
Fig.7  RNA polymerase assembly in infected cells. A: PB1 and PB2 enter the nucleus with the help of PA and HSP90, respectively. The RdRp heterotrimeric complex assembles in the nucleus, releasing HSP90. B: HSP90 escorts the nuclear import of the PB1 and PB2 binary complex by facilitating their association and interaction with the binary complex. Additionally, PA singly enters the nucleus, where the RdRp trimer forms and HSP90 is subsequently released. Modified from Naito et al. ().
Fig.8  Network of host factors and viral factors interacting with RNP. Details are described in the text. The host factors in gray perform functions in viral replication or transcription by unknown mechanisms.
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