2. Academic Validation
  3. Envelope protein ubiquitination drives entry and pathogenesis of Zika virus

Envelope protein ubiquitination drives entry and pathogenesis of Zika virus

  • Nature. 2020 Sep;585(7825):414-419. doi: 10.1038/s41586-020-2457-8.
Maria I Giraldo # 1 2,  Hongjie Xia # 3,  Leopoldo Aguilera-Aguirre 1,  Adam Hage 1,  Sarah van Tol 1,  Chao Shan 3,  Xuping Xie 3,  Gail L Sturdevant 4,  Shelly J Robertson 4,  Kristin L McNally 4,  Kimberly Meade-White 4,  Sasha R Azar 1 5 6,  Shannan L Rossi 6 7,  Wendy Maury 8,  Michael Woodson 9,  Holly Ramage 10,  Jeffrey R Johnson 11 12 13 14,  Nevan J Krogan 11 12 13 14,  Marc C Morais 3 9,  Sonja M Best 4,  Pei-Yong Shi 15 16 17 18 19,  Ricardo Rajsbaum 20 21
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • 2 Centro de Investigaciones Biomédicas, Universidad del Quindío, Armenia, Colombia.
  • 3 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
  • 4 Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
  • 5 Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, USA.
  • 6 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
  • 7 Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • 8 Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
  • 9 Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA.
  • 10 Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.
  • 11 Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • 12 Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
  • 13 Gladstone Institute for Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA.
  • 14 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 15 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA. peshi@utmb.edu.
  • 16 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA. peshi@utmb.edu.
  • 17 Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA. peshi@utmb.edu.
  • 18 Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA. peshi@utmb.edu.
  • 19 Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA. peshi@utmb.edu.
  • 20 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA. rirajsba@utmb.edu.
  • 21 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA. rirajsba@utmb.edu.
  • # Contributed equally.
PMID: 32641828 DOI: 10.1038/s41586-020-2457-8
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.

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