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; Ricardo Rajsbaum

doi:10.1038/s41586-020-2457-8

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

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105 Scopus citations

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 tissues^1–3. 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 language	English (US)
Pages (from-to)	414-419
Number of pages	6
Journal	Nature
Volume	585
Issue number	7825
DOIs	https://doi.org/10.1038/s41586-020-2457-8
State	Published - Sep 17 2020

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Giraldo, M. I., Xia, H., Aguilera-Aguirre, L., Hage, A., van Tol, S., Shan, C., Xie, X., Sturdevant, G. L., Robertson, S. J., McNally, K. L., Meade-White, K., Azar, S. R., Rossi, S. L., Maury, W., Woodson, M., Ramage, H., Johnson, J. R., Krogan, N. J., Morais, M. C., ... Rajsbaum, R. (2020). Envelope protein ubiquitination drives entry and pathogenesis of Zika virus. Nature, 585(7825), 414-419. https://doi.org/10.1038/s41586-020-2457-8

Giraldo, MI, Xia, H, Aguilera-Aguirre, L, Hage, A, van Tol, S, Shan, C, Xie, X, Sturdevant, GL, Robertson, SJ, McNally, KL, Meade-White, K, Azar, SR, Rossi, SL, Maury, W, Woodson, M, Ramage, H, Johnson, JR, Krogan, NJ, Morais, MC, Best, SM, Shi, PY & Rajsbaum, R 2020, 'Envelope protein ubiquitination drives entry and pathogenesis of Zika virus', Nature, vol. 585, no. 7825, pp. 414-419. https://doi.org/10.1038/s41586-020-2457-8

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title = "Envelope protein ubiquitination drives entry and pathogenesis of Zika virus",

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.",

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

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doi = "10.1038/s41586-020-2457-8",

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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 R.

AU - Rossi, Shannan L.

AU - Maury, Wendy

AU - Woodson, Michael

AU - Ramage, Holly

AU - Johnson, Jeffrey R.

AU - Krogan, Nevan J.

AU - Morais, Marc C.

AU - Best, Sonja M.

AU - Shi, Pei Yong

AU - Rajsbaum, Ricardo

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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VL - 585

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EP - 419

JO - Nature

JF - Nature

IS - 7825

ER -

Envelope protein ubiquitination drives entry and pathogenesis of Zika virus

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