A Mechanism for the Activation of the Influenza Virus Transcriptase

Martin, I. Serna; Hengrung, Narin; Renner, Max; Sharps, Jane; Martínez-Alonso, Maira; Masiulis, Simonas; Grimes, Jonathan M.; Fodor, Ervin

doi:10.1016/j.molcel.2018.05.011

Cited by 51 publications

(85 citation statements)

References 45 publications

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“…PB2 also interacts with the C-terminal domain of RNA polymerase II, and this interaction is proposed to stabilize the polymerase in the transcription-competent conformation (PDB: 6F5O) (Serna Martin et al, 2018). Similar to what we observe with importin-a, PB2 sites thought to directly interact with RNA polymerase II tend to have low differential selection, whereas adjacent PB2 sites have higher differential selection ( Fig S5C).…”

Section: Human-adaptive Mutations Cluster In Regions Of Pb2 That Are supporting

confidence: 71%

Comprehensive mapping of avian influenza polymerase adaptation to the human host

Soh

Moncla

Eguia

et al. 2019

Preprint

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Viruses like influenza are infamous for their ability to adapt to new hosts. Retrospective studies of natural zoonoses and passaging in the lab have identified a modest number of host-adaptive mutations. However, it is unclear if these mutations represent all ways that influenza can adapt to a new host. Here we take a prospective approach to this question by completely mapping amino-acid mutations to the avian influenza virus polymerase protein PB2 that enhance growth in human cells. We identify numerous previously uncharacterized human-adaptive mutations. These mutations cluster on PB2's surface, highlighting potential interfaces with host factors. Some previously uncharacterized adaptive mutations occur in avian-to-human transmission of H7N9 influenza, showing their importance for natural virus evolution. But other adaptive mutations do not occur in nature because they are inaccessible via single-nucleotide mutations. Overall, our work shows how selection at key molecular surfaces combines with evolutionary accessibility to shape viral host adaptation.

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Section: Human-adaptive Mutations Cluster In Regions Of Pb2 That Are supporting

confidence: 71%

Comprehensive mapping of avian influenza polymerase adaptation to the human host

Soh

Moncla

Eguia

et al. 2019

Preprint

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“…They are responsible for interacting with the terminal ends of viral promoters and for catalyzing the nucleotidyl transfer reaction. The core also binds the Ser5-phosphorylated CTD (Lukarska et al, 2017;Martin et al, 2018). Influenza RdRp binds to m 7 G on nascent host RNAs through a cap-binding domain on the vRdRp C terminus of PB2 (PB2-C) subunit (Fechter et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase

Tang

et al. 2020

Front. Microbiol.

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Influenza virus RNA-dependent RNA polymerase (vRdRp) does not have capping activity and relies on the capped RNAs produced by the host RNA polymerase II (RNAPII). The viral polymerases process the capped RNAs to produce short capped RNA fragments that are used as primers to initiate the transcription of viral mRNAs. This process, known as cap-snatching, can be targeted by antiviral therapeutics. Here, anthralin was identified as an inhibitor against influenza a virus (IAV) infection by targeting the capsnatching activity of the viral polymerase. Anthralin, an FDA-approved drug used in the treatment of psoriasis, shows antiviral activity against IAV infection in vitro and in vivo. Importantly, anthralin significantly reduces weight loss, lung injury, and mortality caused by IAV infection in mice. The mechanism of action study revealed that anthralin inhibits the cap-binding function of PB2 subunit and endonuclease activity of PA. As a result, viral mRNA transcription is blocked, leading to the decreases in viral RNA replication and viral protein expression. In conclusion, anthralin has been demonstrated to have the potential of an alternative antiviral against influenza virus infection. Also, targeting the captive pocket structure that includes the N-terminus of PA endonuclease domain and the C-terminal of PB2 cap-binding domain of IAV RdRp may be an excellent strategy for developing anti-influenza drugs.

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“…First, the RNA polymerase associated with vRNPs, that is, the resident polymerase, binds the carboxy-terminal domain (CTD) of the large subunit of host RNA polymerase II (Pol II) to bring vRNPs in close proximity to nascent host 5 0 capped RNAs ( Fig. 3A; Engelhardt et al 2005;Martínez-Alonso et al 2016;Lukarska et al 2017;Serna Martin et al 2018). Pol II CTD interacts with the viral RNA polymerase at several binding sites (Lukarska et al 2017;Serna Martin et al 2018), which stabilizes the PB2 cap-binding and PA endonuclease domains in a transcription-ready conformation (Serna Martin et al 2018).…”

Section: Transcriptionmentioning

confidence: 99%

“…3A; Engelhardt et al 2005;Martínez-Alonso et al 2016;Lukarska et al 2017;Serna Martin et al 2018). Pol II CTD interacts with the viral RNA polymerase at several binding sites (Lukarska et al 2017;Serna Martin et al 2018), which stabilizes the PB2 cap-binding and PA endonuclease domains in a transcription-ready conformation (Serna Martin et al 2018). Second, the PB2 cap-binding domain binds the 5 0 cap of the nascent host RNA and the PA endonuclease Figure 2.…”

Section: Transcriptionmentioning

confidence: 99%

“…The transcriptional activity of the viral RNA polymerase is dependent on host Pol II for capped RNA primers that facilitate transcription initiation (Plotch et al 1981) and structural studies have shown that the interaction of the viral polymerase with the CTD of Pol II is important for stabilizing a conformation of the viral polymerase that is competent in capsnatching and transcription initiation ( Fig. 3A; Lukarska et al 2017;Serna Martin et al 2018). ANP32 proteins have been identified as further host factors that are essential for viral polymerase activity.…”

Section: Host Factors and Adaptive Mutationsmentioning

confidence: 99%

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Structure and Function of the Influenza Virus Transcription and Replication Machinery

Fodor

Velthuis

2019

Cold Spring Harb Perspect Med

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107

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Transcription and replication of the influenza virus RNA genome is catalyzed by the viral heterotrimeric RNA-dependent RNA polymerase in the context of viral ribonucleoprotein (vRNP) complexes. Atomic resolution structures of the viral RNA synthesis machinery have offered insights into the initiation mechanisms of viral transcription and genome replication, and the interaction of the viral RNA polymerase with host RNA polymerase II, which is required for the initiation of viral transcription. Replication of the viral RNA genome by the viral RNA polymerase depends on host ANP32A, and host-specific sequence differences in ANP32A underlie the poor activity of avian influenza virus polymerases in mammalian cells. A failure to faithfully copy the viral genome segments can lead to the production of aberrant viral RNA products, such as defective interfering (DI) RNAs and mini viral RNAs (mvRNAs). Both aberrant RNA types have been implicated in innate immune responses against influenza virus infection. This review discusses recent insights into the structure-function relationship of the viral RNA polymerase and its role in determining host range and virulence.

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A Mechanism for the Activation of the Influenza Virus Transcriptase

Cited by 51 publications

References 45 publications

Comprehensive mapping of avian influenza polymerase adaptation to the human host

Comprehensive mapping of avian influenza polymerase adaptation to the human host

Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase

Structure and Function of the Influenza Virus Transcription and Replication Machinery

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