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

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, Britta Brügger, Ilpo Vattulainen and Ralf Bartenschlager ()
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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
Giulia Mizzon: Center for Integrative Infectious Diseases Research
Leander Witte: Center for Integrative Infectious Diseases Research
Waldemar Kulig: University of Helsinki
Zina M. Uckeley: Virology, Center for Integrative Infectious Diseases Research
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
Britta Brügger: Heidelberg University Biochemistry Center (BZH)
Ilpo Vattulainen: University of Helsinki
Ralf Bartenschlager: Center for Integrative Infectious Diseases Research

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42985-x

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