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Zika virus prM protein contains cholesterol binding motifs required for virus entry and assembly

Author

Listed:
  • Sarah Goellner

    (Center for Integrative Infectious Diseases Research)

  • Giray Enkavi

    (University of Helsinki)

  • Vibhu Prasad

    (Center for Integrative Infectious Diseases Research)

  • Solène Denolly

    (Center for Integrative Infectious Diseases Research)

  • Sungmin Eu

    (Center for Integrative Infectious Diseases Research
    d-fine GmbH)

  • Giulia Mizzon

    (Center for Integrative Infectious Diseases Research
    Heidelberg partner site)

  • Leander Witte

    (Center for Integrative Infectious Diseases Research)

  • Waldemar Kulig

    (University of Helsinki)

  • Zina M. Uckeley

    (Virology, Center for Integrative Infectious Diseases Research
    University of Florida)

  • Teresa M. Lavacca

    (Center for Integrative Infectious Diseases Research)

  • Uta Haselmann

    (Center for Integrative Infectious Diseases Research)

  • Pierre-Yves Lozach

    (Virology, Center for Integrative Infectious Diseases Research
    University of Lyon)

  • Britta Brügger

    (Heidelberg University Biochemistry Center (BZH))

  • Ilpo Vattulainen

    (University of Helsinki)

  • Ralf Bartenschlager

    (Center for Integrative Infectious Diseases Research
    Heidelberg partner site
    German Cancer Research Center (DKFZ))

Abstract

For successful infection of host cells and virion production, enveloped viruses, including Zika virus (ZIKV), extensively rely on cellular lipids. However, how virus protein–lipid interactions contribute to the viral life cycle remains unclear. Here, we employ a chemo-proteomics approach with a bifunctional cholesterol probe and show that cholesterol is closely associated with the ZIKV structural protein prM. Bioinformatic analyses, reverse genetics alongside with photoaffinity labeling assays, and atomistic molecular dynamics simulations identified two functional cholesterol binding motifs within the prM transmembrane domain. Loss of prM–cholesterol association has a bipartite effect reducing ZIKV entry and leading to assembly defects. We propose a model in which membrane-resident M facilitates cholesterol-supported lipid exchange during endosomal entry and, together with cholesterol, creates a platform promoting virion assembly. In summary, we identify a bifunctional role of prM in the ZIKV life cycle by mediating viral entry and virus assembly in a cholesterol-dependent manner.

Suggested Citation

  • Sarah Goellner & Giray Enkavi & Vibhu Prasad & Solène Denolly & Sungmin Eu & Giulia Mizzon & Leander Witte & Waldemar Kulig & Zina M. Uckeley & Teresa M. Lavacca & Uta Haselmann & Pierre-Yves Lozach &, 2023. "Zika virus prM protein contains cholesterol binding motifs required for virus entry and assembly," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42985-x
    DOI: 10.1038/s41467-023-42985-x
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    References listed on IDEAS

    as
    1. Max Renner & Wanwisa Dejnirattisai & Loïc Carrique & Itziar Serna Martin & Dimple Karia & Serban L. Ilca & Shu F. Ho & Abhay Kotecha & Jeremy R. Keown & Juthathip Mongkolsapaya & Gavin R. Screaton & J, 2021. "Flavivirus maturation leads to the formation of an occupied lipid pocket in the surface glycoproteins," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    2. Moritz Hacke & Patrik Björkholm & Andrea Hellwig & Patricia Himmels & Carmen Ruiz de Almodóvar & Britta Brügger & Felix Wieland & Andreas M. Ernst, 2015. "Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    3. Nadia M. DiNunno & Daniel J. Goetschius & Anoop Narayanan & Sydney A. Majowicz & Ibrahim Moustafa & Carol M. Bator & Susan L. Hafenstein & Joyce Jose, 2020. "Identification of a pocket factor that is critical to Zika virus assembly," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    4. Ter Yong Tan & Guntur Fibriansah & Victor A. Kostyuchenko & Thiam-Seng Ng & Xin-Xiang Lim & Shuijun Zhang & Xin-Ni Lim & Jiaqi Wang & Jian Shi & Marc C. Morais & Davide Corti & Shee-Mei Lok, 2020. "Capsid protein structure in Zika virus reveals the flavivirus assembly process," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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