![]() ![]() It is currently unclear which cytoplasmic capped RNAs are accessed by bunyavirus polymerases, and in what context, and if the polymerase contains specific domains that interact with host capped-RNA-bound proteins. Whereas influenza polymerase interacts directly with the host RNA polymerase II to snatch the caps of nascent transcripts in the nucleus 7, bunyavirus polymerases act in the cytoplasm. Transcription is initiated by a “cap-snatching” mechanism, whereby host 5′ capped RNAs are bound by the L cap-binding domain (CBD), cleaved by the L endonuclease domain several nucleotides downstream, and then used to prime synthesis of mRNA 2, 5, 6.Īlthough the overall mechanism of transcription initiation is likely conserved between sNSVs, several elements suggest some divergence between viral families. ![]() Replication generates full-length genome or antigenome copies (vRNA and cRNA, respectively), whereas transcription produces capped viral mRNA that are recognized by the cellular translation machinery to produce viral proteins. These processes are performed in the cytoplasm of infected cells for Bunyaviruses, whereas they occur in the nucleus for influenza virus 3, 4. Replication and transcription of sNSV viral genomic segments are performed by the virally encoded RNA-dependent RNA polymerase, also called L protein for Bunyavirales 2. Viruses from the Bunyavirales order are related to other sNSV and in particular to influenza virus, a major human pathogen belonging to the Orthomyxoviridae family. It contains serious human pathogens such as La Crosse virus (LACV, Peribunyaviridae family), Hantaan virus (HTNV, Hantaviridae family), Crimean-Congo hemorrhagic fever virus (CCHFV, Nairoviridae family), Rift Valley Fever virus (RVFV, Phenuiviridae family), and Lassa fever virus (LASV, Arenaviridae family). These structural details and the observed dynamics of key functional elements will be instrumental for structure-based development of polymerase inhibitors.īunyavirales is a very large and diverse order of segmented negative-strand RNA viruses (sNSV) comprising more than 500 species classified into 12 families 1. We capture the polymerase structure at pre-initiation and elongation states, uncovering the coordinated movement of the priming loop, mid-thumb ring linker and lid domain required for the establishment of a ten-base-pair template-product RNA duplex before strand separation into respective exit tunnels. It reveals the presence of key protruding C-terminal domains, notably the cap-binding domain, which undergoes large movements related to its role in transcription initiation, and a zinc-binding domain that displays a fold not previously observed. Here, we describe the complete high-resolution cryo-EM structure of La Crosse virus polymerase. Replication and transcription of the RNA genome constitute essential processes performed by the virally encoded multi-domain RNA-dependent RNA polymerase. Bunyavirales is an order of segmented negative-strand RNA viruses comprising several life-threatening pathogens against which no effective treatment is currently available.
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