Review The Cap-Snatching Mechanism of Bunyaviruses Silke Olschewski, 1 Stephen Cusack, 2 and Maria Rosenthal 1, * In common with all segmented negative-sense RNA viruses, bunyavirus tran- scripts contain heterologous sequences at their 5′ termini originating from capped host cell RNAs. These heterologous sequences are acquired by a so- called cap-snatching mechanism. Whereas for nuclear replicating influenza virus the source of capped primers as well as the cap-binding and endonuclease activities of the viral polymerase needed for cap snatching have been function- ally and structurally well characterized, our knowledge on the expected counter- parts of cytoplasmic replicating bunyaviruses is still limited and controversial. This review focuses on the cap-snatching mechanism of bunyaviruses in the light of recent structural and functional data. Bunyavirus Transcription and Genome Replication The order of Bunyavirales, which was established in 2018, accommodates a diverse group of viruses formerly separated into the Arenaviridae and Bunyaviridae families [ 1]. The Bunyavirales order contains important human pathogens such as Lassa virus (LASV; family Arenaviridae), Crimean-Congo hemorrhagic fever virus (family Nairoviridae), Rift Valley fever virus (RVFV, family Phenuiviridae), Hantaan virus (family Hantaviridae), and La Crosse virus (family Peribunyaviridae). Bunyaviruses contain a segmented single-stranded RNA genome with negative polarity, although viruses of the Arenaviridae and Phenuiviridae families use an ambisense coding strategy (see Glossary)[2]. The viral genome segments are associated with the nucleoprotein (N) and the large (L) protein forming ribonucleoprotein complexes (RNPs), which are the functional units of viral genome replication and transcription. The processes of genome replication and transcrip- tion are catalyzed by the L protein, which among other functions contains an RNA-dependent RNA polymerase [3]. Viral transcription and genome replication require different mechanisms. Whereas during genome replication identical genome copies are produced, viral transcription re- sults in capped, mostly nonpolyadenylated viral mRNAs. Only for some hantavirus mRNAs a polyadenylation has been described due to transcription termination at a poly-U stretch [4]. Ge- nome replication is initiated de novo by the L protein using a prime-and-realign mechanism through a complementary RNA intermediate (cRNA or antigenome) [5–9]. Sequencing identified heterologous non-viral sequences at the 5′ termini of bunyavirus mRNAs (Table 1). Therefore, it was concluded that bunyaviruses use a cap-snatching mechanism to prime viral transcription, as do the related orthomyxoviruses (e.g., influenza virus). Influenza virus cap-snatching works as follows: the polymerase complex binds to the cap structure of cellular RNAs by means of a cap-binding domain (CBD) in the PB2 subunit. An endonuclease in the PA subunit cleaves this RNA 10–15 nucleotides downstream of the cap producing a capped RNA fragment, which is subsequently used to prime viral transcription [10]. There is also evidence that transcription ini- tiation in segmented negative-strand viruses can be associated with several rounds of prime-and- realign depending on the host primer length and degree of complementarity with the first bases of the viral template RNA [11–14]. The activities of influenza virus polymerase needed for cap Highlights Endonuclease domains have been lo- cated in many different bunyavirus L pro- teins and can be classified as His+ or His– metal-dependent endonucleases. An active cap-binding domain (CBD) has been identified in the C-terminal region of bunyavirus L protein. Despite very low sequence identity, this domain is very similar to influenza virus PB2 CBD on the structural level. Atomic structures of bunyavirus N pro- tein do not provide evidence for the hy- pothesized N protein cap-binding site. It remains unclear whether a functionally relevant cap-specific binding site exists in any bunyavirus N protein. The comparably low affinity of bunyavirus CBD for cap-structures indicates the ne- cessity for further regions of the L protein or other viral or cellular proteins to be in- volved in cap binding. 1 Bernhard Nocht Institute for Tropical Medicine, Department of Virology, Ham- burg, Germany 2 European Molecular Biology Laboratory, Grenoble, France *Correspondence: [email protected] (M. Rosenthal). Trends in Microbiology, April 2020, Vol. 28, No. 4 https://doi.org/10.1016/j.tim.2019.12.006 293 © 2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Trends in Microbiology
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