Envelope protein ubiquitination drives entry and pathogenesis of Zika virus

Nature. 2020 Sep;585(7825):414-419. doi: 10.1038/s41586-020-2457-8. Epub 2020 Jul 8.


Zika virus (ZIKV) belongs to the family Flaviviridae, and is related to other viruses that cause human diseases. Unlike other flaviviruses, ZIKV infection can cause congenital neurological disorders and replicates efficiently in reproductive tissues1-3. Here we show that the envelope protein (E) of ZIKV is polyubiquitinated by the E3 ubiquitin ligase TRIM7 through Lys63 (K63)-linked polyubiquitination. Accordingly, ZIKV replicates less efficiently in the brain and reproductive tissues of Trim7-/- mice. Ubiquitinated E is present on infectious virions of ZIKV when they are released from specific cell types, and enhances virus attachment and entry into cells. Specifically, K63-linked polyubiquitin chains directly interact with the TIM1 (also known as HAVCR1) receptor of host cells, which enhances virus entry in cells as well as in brain tissue in vivo. Recombinant ZIKV mutants that lack ubiquitination are attenuated in human cells and in wild-type mice, but not in live mosquitoes. Monoclonal antibodies against K63-linked polyubiquitin specifically neutralize ZIKV and reduce viraemia in mice. Our results demonstrate that the ubiquitination of ZIKV E is an important determinant of virus entry, tropism and pathogenesis.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology
  • Brain / metabolism
  • Cell Line
  • Culicidae / cytology
  • Culicidae / virology
  • Endosomes / metabolism
  • Female
  • Hepatitis A Virus Cellular Receptor 1 / metabolism
  • Humans
  • Male
  • Membrane Fusion
  • Mice
  • Organ Specificity
  • Polyubiquitin / immunology
  • Polyubiquitin / metabolism
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination*
  • Viral Envelope Proteins / chemistry*
  • Viral Envelope Proteins / metabolism*
  • Viral Tropism
  • Viremia / immunology
  • Viremia / prevention & control
  • Viremia / virology
  • Virus Internalization*
  • Virus Replication
  • Zika Virus / chemistry
  • Zika Virus / genetics
  • Zika Virus / metabolism*
  • Zika Virus / pathogenicity*
  • Zika Virus Infection / prevention & control
  • Zika Virus Infection / virology


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Tripartite Motif Proteins
  • Viral Envelope Proteins
  • Polyubiquitin
  • TRIM7 protein, human
  • Ubiquitin-Protein Ligases