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Envelope protein ubiquitination drives entry and pathogenesis of Zika virus

Author

Listed:
  • Maria I. Giraldo

    (University of Texas Medical Branch
    Universidad del Quindío)

  • Hongjie Xia

    (University of Texas Medical Branch)

  • Leopoldo Aguilera-Aguirre

    (University of Texas Medical Branch)

  • Adam Hage

    (University of Texas Medical Branch)

  • Sarah van Tol

    (University of Texas Medical Branch)

  • Chao Shan

    (University of Texas Medical Branch)

  • Xuping Xie

    (University of Texas Medical Branch)

  • Gail L. Sturdevant

    (National Institutes of Health)

  • Shelly J. Robertson

    (National Institutes of Health)

  • Kristin L. McNally

    (National Institutes of Health)

  • Kimberly Meade-White

    (National Institutes of Health)

  • Sasha R. Azar

    (University of Texas Medical Branch
    University of Texas Medical Branch
    University of Texas Medical Branch)

  • Shannan L. Rossi

    (University of Texas Medical Branch
    University of Texas Medical Branch)

  • Wendy Maury

    (University of Iowa)

  • Michael Woodson

    (University of Texas Medical Branch)

  • Holly Ramage

    (University of Pennsylvania)

  • Jeffrey R. Johnson

    (University of California San Francisco
    University of California San Francisco
    Gladstone Institutes
    Icahn School of Medicine at Mount Sinai)

  • Nevan J. Krogan

    (University of California San Francisco
    University of California San Francisco
    Gladstone Institutes
    Icahn School of Medicine at Mount Sinai)

  • Marc C. Morais

    (University of Texas Medical Branch
    University of Texas Medical Branch)

  • Sonja M. Best

    (National Institutes of Health)

  • Pei-Yong Shi

    (University of Texas Medical Branch
    University of Texas Medical Branch
    University of Texas Medical Branch
    University of Texas Medical Branch)

  • Ricardo Rajsbaum

    (University of Texas Medical Branch
    University of Texas Medical Branch)

Abstract

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.

Suggested Citation

  • 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 &, 2020. "Envelope protein ubiquitination drives entry and pathogenesis of Zika virus," Nature, Nature, vol. 585(7825), pages 414-419, September.
  • Handle: RePEc:nat:nature:v:585:y:2020:i:7825:d:10.1038_s41586-020-2457-8
    DOI: 10.1038/s41586-020-2457-8
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    Cited by:

    1. Yuege Huang & Hong Mei & Chunchen Deng & Wei Wang & Chao Yuan & Yan Nie & Jia-Da Li & Jia Liu, 2024. "EXTL3 and NPC1 are mammalian host factors for Autographa californica multiple nucleopolyhedrovirus infection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Linliang Zhang & Hongyun Wang & Chao Han & Qi Dong & Jie Yan & Weiwei Guo & Chao Shan & Wen Zhao & Pu Chen & Rui Huang & Ying Wu & Yu Chen & Yali Qin & Mingzhou Chen, 2024. "AMFR-mediated Flavivirus NS2A ubiquitination subverts ER-phagy to augment viral pathogenicity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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