Envelope protein ubiquitination drives entry and pathogenesis of Zika virus

Maria I. Giraldo, Hongjie Xia, Leopoldo Aguilera-Aguirre, Adam Hage, Sarah van Tol, Chao Shan, Xuping Xie, Gail L. Sturdevant, Shelly J. Robertson, Kristin L. McNally, Kimberly Meade-White, Sasha R. Azar, Shannan L. Rossi, Wendy Maury, Michael Woodson, Holly Ramage, Jeffrey R. Johnson, Nevan J. Krogan, Marc C. Morais, Sonja M. BestPei Yong Shi, Ricardo Rajsbaum

    Research output: Contribution to journalArticlepeer-review

    82 Scopus citations


    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.

    Original languageEnglish (US)
    Pages (from-to)414-419
    Number of pages6
    Issue number7825
    StatePublished - Sep 17 2020

    ASJC Scopus subject areas

    • General


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