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

Author

Listed:
  • Vasiliya Kril

    (Hôpital Saint Louis)

  • Michael Hons

    (European Molecular Biology Laboratory
    Deutsches Elektronen Synchrotron DESY)

  • 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
    Viral Macromolecular Complexes Team)

  • Denis Ptchelkine

    (CNRS)

  • Alexandra L. Thienel

    (University of Bonn)

  • Beate M. Kümmerer

    (University of Bonn)

  • Ambroise Desfosses

    (IBS)

  • Rhian Jones

    (CNRS
    Viral Macromolecular Complexes Team)

  • Philippe Roingeard

    (INSERM U1259 MAVIVH et Plateforme IBiSA de Microscopie Electronique)

  • Laurent Meertens

    (Hôpital Saint Louis)

  • Ali Amara

    (Hôpital Saint Louis)

  • Juan Reguera

    (CNRS
    Viral Macromolecular Complexes Team)

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.

Suggested Citation

  • 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, 2024. "Alphavirus nsP3 organizes into tubular scaffolds essential for infection and the cytoplasmic granule architecture," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51952-z
    DOI: 10.1038/s41467-024-51952-z
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    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Rhian Jones & Gabriel Bragagnolo & Rocío Arranz & Juan Reguera, 2021. "Capping pores of alphavirus nsP1 gate membranous viral replication factories," Nature, Nature, vol. 589(7843), pages 615-619, January.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    4. Laurent Meertens & Mohamed Lamine Hafirassou & Thérèse Couderc & Lucie Bonnet-Madin & Vasiliya Kril & Beate M. Kümmerer & Athena Labeau & Alexis Brugier & Etienne Simon-Loriere & Julien Burlaud-Gailla, 2019. "FHL1 is a major host factor for chikungunya virus infection," Nature, Nature, vol. 574(7777), pages 259-263, October.
    5. Wern Hann Ng & Xiang Liu & Zheng L. Ling & Camilla N. O. Santos & Lucas S. Magalhães & Andrew J. Kueh & Marco J. Herold & Adam Taylor & Joseph R. Freitas & Sandra Koit & Sainan Wang & Andrew R. Lloyd , 2023. "FHL1 promotes chikungunya and o’nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
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