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. Best, Pei-Yong Shi () and Ricardo Rajsbaum ()
Additional contact information
Maria I. Giraldo: University of Texas Medical Branch
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
Shannan L. Rossi: 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
Nevan J. Krogan: University of California San Francisco
Marc C. Morais: University of Texas Medical Branch
Sonja M. Best: National Institutes of Health
Pei-Yong Shi: University of Texas Medical Branch
Ricardo Rajsbaum: University of Texas Medical Branch

Nature, 2020, vol. 585, issue 7825, 414-419

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2457-8

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