Alphavirus nsP3 organizes into tubular scaffolds essential for infection and the cytoplasmic granule architecture

Vasiliya Kril, Michael Hons, Celine Amadori, Claire Zimberger, Laurine Couture, Yara Bouery, Julien Burlaud-Gaillard, Andrei Karpov, Denis Ptchelkine, Alexandra L. Thienel, Beate M. Kümmerer, Ambroise Desfosses, Rhian Jones, Philippe Roingeard, Laurent Meertens, Ali Amara () and Juan Reguera ()
Additional contact information
Vasiliya Kril: Hôpital Saint Louis
Michael Hons: European Molecular Biology Laboratory
Celine Amadori: Hôpital Saint Louis
Claire Zimberger: CNRS
Laurine Couture: Hôpital Saint Louis
Yara Bouery: Hôpital Saint Louis
Julien Burlaud-Gaillard: INSERM U1259 MAVIVH et Plateforme IBiSA de Microscopie Electronique
Andrei Karpov: Turing Centre for Living Systems
Denis Ptchelkine: CNRS
Alexandra L. Thienel: University of Bonn
Beate M. Kümmerer: University of Bonn
Ambroise Desfosses: IBS
Rhian Jones: CNRS
Philippe Roingeard: INSERM U1259 MAVIVH et Plateforme IBiSA de Microscopie Electronique
Laurent Meertens: Hôpital Saint Louis
Ali Amara: Hôpital Saint Louis
Juan Reguera: CNRS

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Alphaviruses, such as chikungunya virus (CHIKV), are mosquito-borne viruses that represent a significant threat to human health due to the current context of global warming. Efficient alphavirus infection relies on the activity of the non-structural protein 3 (nsP3), a puzzling multifunctional molecule whose role in infection remains largely unknown. NsP3 is a component of the plasma membrane-bound viral RNA replication complex (vRC) essential for RNA amplification and is also found in large cytoplasmic aggregates of unknown function. Here, we report the cryo-electron microscopy (cryo-EM) structure of the CHIKV nsP3 at 2.35 Å resolution. We show that nsP3 assembles into tubular structures made by a helical arrangement of its alphavirus unique domain (AUD). The nsP3 helical scaffolds are consistent with crown structures found on tomographic reconstructions of the mature viral RCs. In addition, nsP3 helices assemble into cytoplasmic granules organized in a network of tubular structures that contain viral genomic RNA and capsid as well as host factors required for productive infection. Structure-guided mutagenesis identified residues that prevent or disturb nsP3 assemblies, resulting in impaired viral replication or transcription. Altogether, our results reveal an unexpected nsP3-dependent molecular organization essential for different phases of alphavirus infection.

Date: 2024
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DOI: 10.1038/s41467-024-51952-z

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