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

Cell. 2018 Dec 13;175(7):1931-1945.e18. doi: 10.1016/j.cell.2018.11.028.


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.

Keywords: ANKLE2; Drosophila; PAF1C; Sec61; Zika virus; dengue virus; endoplasmic reticulum; flavivirus; interferon stimulated genes; microcephaly; proteomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Culicidae
  • Dengue Virus* / genetics
  • Dengue Virus* / metabolism
  • Dengue Virus* / pathogenicity
  • Dengue* / genetics
  • Dengue* / metabolism
  • Dengue* / pathology
  • HEK293 Cells
  • Humans
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Protein Interaction Mapping
  • Viral Nonstructural Proteins* / genetics
  • Viral Nonstructural Proteins* / metabolism
  • Zika Virus Infection* / genetics
  • Zika Virus Infection* / metabolism
  • Zika Virus Infection* / pathology
  • Zika Virus* / genetics
  • Zika Virus* / metabolism
  • Zika Virus* / pathogenicity


  • ANKLE2 protein, human
  • Membrane Proteins
  • NS4A protein, Dengue virus
  • NS5 protein, dengue virus
  • Nuclear Proteins
  • Viral Nonstructural Proteins