The Influenza Virus RNA-polymerase and the Host RNA-Polymerase II: RPB4 is Targeted by a PB2 Domain that is Involved in Viral Transcription

Morel, Jessica; Sedano, Laura; Lejal, Nathalie; Costa, Bruno Da; Batsché, Éric; Muchardt, Christian; Delmas, Bernard

doi:10.20944/preprints202202.0170.v1

Cited by 2 publications

References 38 publications

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Structural and functional characterisation of the interaction between the influenza A virus RNA polymerase and the CTD of host RNA Polymerase II

Keown,

Baazaoui,

Šebesta

et al. 2023

Preprint

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Influenza A viruses (IAV), causing seasonal epidemics and occasional pandemics, rely on interactions with host proteins for their RNA genome transcription and replication. The viral RNA polymerase utilizes host RNA polymerase II (Pol II) and interacts with the serine 5 phosphorylated (pS5) C-terminal domain (CTD) of Pol II to initiate transcription. Our study, using single-particle electron cryomicroscopy (cryo-EM), reveals the structure of the 1918 pandemic IAV polymerase bound to a synthetic pS5 CTD heptad repeat peptide. The structure shows that the CTD peptide binds at the C-terminal domain of the PA viral polymerase subunit (PA-C) and reveals a previously unobserved position of the 627 domain of the PB2 subunit near the CTD. We identify crucial residues of the CTD peptide mediating interactions with positively charged cavities on PA-C, explaining the preference of the viral polymerase for pS5 CTD. Functional analysis of mutants targeting the CTD-binding site within PA-C reveals reduced transcriptional function with normal replication, while other mutants display defects in both transcription and replication, highlighting the multifunctional role of PA-C in viral RNA synthesis. Our study provides insights into the structural and functional aspects of the influenza virus polymerase-host Pol II interaction and identifies a target for antiviral development.

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Structural and functional characterisation of the interaction between the influenza A virus RNA polymerase and the CTD of host RNA Polymerase II

Keown,

Baazaoui,

Šebesta

et al. 2023

Preprint

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Host-Specific Interplay between Foot-and-Mouth Disease Virus 3D Polymerase and the Type-I Interferon Pathway

Sarry

Caignard

Dupré

et al. 2023

Viruses

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Foot-and-mouth disease (FMD) is a highly contagious viral disease affecting cloven-hoofed animals. One of the issues related to this disease is the persistence of its causative agent, foot-and-mouth disease virus (FMDV). While the mechanisms of FMDV persistence remain unclear, there are clues that it may be related to protein–protein interactions (PPI) between viral proteins and cellular proteins involved in the interferon (IFN) response. Since FMDV persistence has been described in cattle, sheep and goats but not in swine, we screened PPI involving FMDV proteins and sixteen major type-I IFN pathway proteins from these four species by nanoluciferase-2-hybrid complementation assay, in order to identify new PPI and determine their host specificity. As the results concerning the 3Dpol were the most interesting in view of the limited data concerning its role in immune escape, we decided to focus particularly on this protein. The identified PPI were confirmed by GST pull-down. We identified PPI between 3Dpol and seven IFN pathway proteins, namely, IKKα, IKKε, IRF3, IRF7, NEMO, MDA5 and MAVS. These PPI are conserved among the four studied species, with the exception of the one between 3Dpol and MAVS, which was only found with the swine protein. We also showed, using luciferase reporter assays, that 3Dpol could inhibit the induction phase of the IFN pathway. These results demonstrate, for the first time, a putative role for 3Dpol in FMDV innate immune escape.

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The Influenza Virus RNA-polymerase and the Host RNA-Polymerase II: RPB4 is Targeted by a PB2 Domain that is Involved in Viral Transcription

Cited by 2 publications

References 38 publications

Structural and functional characterisation of the interaction between the influenza A virus RNA polymerase and the CTD of host RNA Polymerase II

Structural and functional characterisation of the interaction between the influenza A virus RNA polymerase and the CTD of host RNA Polymerase II

Host-Specific Interplay between Foot-and-Mouth Disease Virus 3D Polymerase and the Type-I Interferon Pathway

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