TY - JOUR
T1 - Envelope protein ubiquitination drives entry and pathogenesis of Zika virus
AU - Giraldo, Maria I.
AU - Xia, Hongjie
AU - Aguilera-Aguirre, Leopoldo
AU - Hage, Adam
AU - van Tol, Sarah
AU - Shan, Chao
AU - Xie, Xuping
AU - Sturdevant, Gail L.
AU - Robertson, Shelly J.
AU - McNally, Kristin L.
AU - Meade-White, Kimberly
AU - Azar, Sasha
AU - Rossi, Shannan L.
AU - Maury, Wendy
AU - Woodson, Michael
AU - Ramage, Holly
AU - Johnson, Jeffrey R.
AU - Krogan, Nevan J.
AU - Morais, Marc
AU - Best, Sonja M.
AU - Shi, Pei Yong
AU - Rajsbaum Gorodezky, Ricardo
N1 - Funding Information:
Acknowledgements We thank M. A. Garcia-Blanco, S. Bradrick and R. Soto for their generosity in sharing reagents and advice; Y. Liang for his technical advice on flow cytometry; M. Fan for providing the lentivirus to establish stable cell lines that express HA–Ub (pLenti puro HA-Ub), through Addgene; A. Gamarnik, R. Stephens and V. Menachery for suggestions and helpful discussions; T. Wang for providing some control mice; and L. Yeager for editing. The laboratory of R.R. was supported in part by the John Sealy Memorial Endowment Fund for Biomedical Research (UTMB), a research career development award (K12HD052023: BIRCWH program, from NIH ORWH/NICHD), and NIH/NIAID grants R21 AI132479-01, R21 AI126012-01A1 and R01 AI134907-01. S.V.T. was supported by NIH/NIAID T32-AI060549, and A.H. by NIH/NIAID T32 AI007526. P.-Y.S. was supported by NIH grants AI142759, AI134907, AI145617 and UL1TR001439, and awards from the Sealy & Smith Foundation, Kleberg Foundation, John S. Dunn Foundation, Amon G. Carter Foundation, Gilson Longenbaugh Foundation and Summerfield Robert Foundation. The laboratory of S.M.B. was supported in part by the Division of Intramural Research of the NIH/NIAID. J.R.J. and N.J.K. were supported by NIH/NIAID grant U19 AI118610.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/9/17
Y1 - 2020/9/17
N2 - 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.
AB - 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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U2 - 10.1038/s41586-020-2457-8
DO - 10.1038/s41586-020-2457-8
M3 - Article
C2 - 32641828
AN - SCOPUS:85087709672
SN - 0028-0836
VL - 585
SP - 414
EP - 419
JO - Nature
JF - Nature
IS - 7825
ER -