A structural understanding of influenza virus genome replication. Issue 3 (March 2023)

• Record Type: Journal Article
• Authors: Zhu, Zihan; Fodor, Ervin; Keown, Jeremy R.
• Is Part Of: Trends in microbiology. Volume 31:Issue 3(2023)
• Page Start: 308
• Page End: 319
• Publication Date: 2023-03
• Subjects: influenza virus -- RNA polymerase -- viral genome -- RNA replication -- nucleoprotein -- ANP32; Microbiology -- Periodicals; Infection -- Periodicals; Virulence (Microbiology) -- Periodicals; Infection -- Periodicals; Microbiology -- Periodicals; Virulence -- Periodicals; Microbiologie -- Périodiques; Infection -- Périodiques; Virulence (Microbiologie) -- Périodiques; Infection; Microbiology; Virulence (Microbiology); 579
• DOI: 10.1016/j.tim.2022.09.015
• Languages: English
• ISSNs: 0966-842X

Abstract

Abstract: Influenza virus contains a single-stranded negative-sense RNA genome. Replication of the genome is carried out by the viral RNA-dependent RNA polymerase in the context of the viral ribonucleoprotein (RNP) complex, through a positive-sense complementary RNA intermediate. Genome replication is tightly controlled through interactions with accessory viral and host factors. Propelled by developments in recombinant protein expression, and technical improvements in X-ray crystallography and cryo-electron microscopy, snapshots of the replication process have been captured. Here, we review how recent structural data shed light on the molecular mechanisms of influenza virus genome replication, in particular, encapsidation of nascent RNA, de novo RNP assembly, and regulation of replication initiation through interactions with host and viral cues. Highlights: Influenza virus RNA genome replication is carried out by a dimeric form of the influenza virus RNA polymerase with one of the polymerases acting as a replicating polymerase, synthesizing product RNA, and the other acting as an encapsidating polymerase, capturing the nascent RNA product and initiating its assembly into a ribonucleoprotein (RNP) complex. Proteins of the acidic nuclear phosphoprotein 32 (ANP32) family, essential host factors for influenza virus RNA genome replication, bridge the replicating and encapsidating polymerase. The disordered highly acidic C-terminal tail of ANP32 proteins acts as a platform for binding viral nucleoprotein, increasing nucleoprotein density around the site of RNA genome replication, and thus facilitating its recruitment to nascent viral RNA. Using a dimeric form of the viral RNA polymerase to replicate viral genomic RNA could be a general feature of negative-sense RNA viruses.