Structures of influenza A and B replication complexes give insight into avian to human host adaptation and reveal a role of ANP32 as an electrostatic chaperone for the apo-polymerase

• Published in: Nature communications Vol. 15; no. 1; pp. 6910 - 20
• Main Authors: Arragain, Benoît, Krischuns, Tim, Pelosse, Martin, Drncova, Petra, Blackledge, Martin, Naffakh, Nadia, Cusack, Stephen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/326/596/1578; 631/535/1258/1259; Animals; Biochemistry, Molecular Biology; Birds - virology; Cellular structure; Complexity; Conformation; Cryoelectron Microscopy; Disease transmission; DNA-directed RNA polymerase; Humanities and Social Sciences; Humans; Influenza; Influenza A; Influenza A virus - genetics; Influenza A virus - metabolism; Influenza in Birds - metabolism; Influenza in Birds - virology; Influenza, Human - virology; Life Sciences; Mammalian cells; Microbiology and Parasitology; Models, Molecular; Molecular Chaperones - chemistry; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; multidisciplinary; Mutation; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Replicase; Replication; RNA, Viral - chemistry; RNA, Viral - genetics; RNA, Viral - metabolism; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; RNA-Dependent RNA Polymerase - chemistry; RNA-Dependent RNA Polymerase - genetics; RNA-Dependent RNA Polymerase - metabolism; Science; Science (multidisciplinary); Static Electricity; Structural Biology; Virology; Virus Replication
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51007-3

Replication of influenza viral RNA depends on at least two viral polymerases, a parental replicase and an encapsidase, and cellular factor ANP32. ANP32 comprises an LRR domain and a long C-terminal low complexity acidic region (LCAR). Here we present evidence suggesting that ANP32 is recruited to the replication complex as an electrostatic chaperone that stabilises the encapsidase moiety within apo-polymerase symmetric dimers that are distinct for influenza A and B polymerases. The ANP32 bound encapsidase, then forms the asymmetric replication complex with the replicase, which is embedded in a parental ribonucleoprotein particle (RNP). Cryo-EM structures reveal the architecture of the influenza A and B replication complexes and the likely trajectory of the nascent RNA product into the encapsidase. The cryo-EM map of the FluB replication complex shows extra density attributable to the ANP32 LCAR wrapping around and stabilising the apo-encapsidase conformation. These structures give new insight into the various mutations that adapt avian strain polymerases to use the distinct ANP32 in mammalian cells. The influenza virus genome replication complex comprises two viral polymerases and host factor ANP32. Structural studies reveal the complex architecture for influenzas A and B, demonstrate the chaperone role of ANP32 and explain polymerase mutations required for avian to human interspecies transmission.