Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Priya S. Shah, Nichole Link, Gwendolyn M. Jang, Phillip P. Sharp, Tongtong Zhu, Danielle L. Swaney, Jeffrey R. Johnson, John Von Dollen, Holly R. Ramage, Laura Satkamp, Billy Newton, Ruth Hüttenhain, Marine J. Petit, Tierney Baum, Amanda Everitt, Orly Laufman, Michel Tassetto, Michael Shales, Erica Stevenson, Gabriel N. IglesiasLeila Shokat, Shashank Tripathi, Vinod Balasubramaniam, Laurence G. Webb, Sebastian Aguirre, A. Jeremy Willsey, Adolfo Garcia-Sastre, Katherine S. Pollard, Sara Cherry, Andrea V. Gamarnik, Ivan Marazzi, Jack Taunton, Ana Fernandez-Sesma, Hugo J. Bellen, Raul Andino, Nevan J. Krogan

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    88 Citations (Scopus)

    Abstract

    Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms. Comparing protein-protein interactions across dengue and Zika viruses reveals both common mechanisms and functionally distinct pathways contributing to infection outcomes.

    Original languageEnglish
    Pages (from-to)1931-1945.e18
    Number of pages33
    JournalCell
    Volume175
    Issue number7
    DOIs
    Publication statusPublished - 13 Dec 2018

    Keywords

    • ANKLE2
    • dengue virus
    • Drosophila
    • endoplasmic reticulum
    • flavivirus
    • interferon stimulated genes
    • microcephaly
    • PAF1C
    • proteomics
    • Sec61
    • Zika virus

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