Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors

Hongda Li; Laura Saucedo-Cuevas; Ling Yuan; Danica Ross; Anide Johansen; Daniel Sands; Valentina Stanley; Alicia Dione Guemez Gamboa; Anne Gregor; Todd Evans; Shuibing Chen; Lei Tan; Henrik Molina; Nicholas Sheets; Sergey A. Shiryaev; Alexey V. Terskikh; Amy S. Gladfelter; Sujan Shresta; Zhiheng Xu; Joseph G. Gleeson

doi:10.1016/j.neuron.2019.01.010

Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors

Hongda Li, Laura Saucedo-Cuevas, Ling Yuan, Danica Ross, Anide Johansen, Daniel Sands, Valentina Stanley, Alicia Dione Guemez Gamboa, Anne Gregor, Todd Evans, Shuibing Chen, Lei Tan, Henrik Molina, Nicholas Sheets, Sergey A. Shiryaev, Alexey V. Terskikh, Amy S. Gladfelter, Sujan Shresta, Zhiheng Xu, Joseph G. Gleeson^*

^*Corresponding author for this work

Neuroscience

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity. Video Abstract: Mechanisms by which Zika virus leads to microcephaly are poorly understood. Here, Li et al. demonstrate the Zika protease, required for viral replication, associates with host proteins and cleaves Septin-2, a protein required for neural cell division.

Original language	English (US)
Pages (from-to)	1089-1098.e4
Journal	Neuron
Volume	101
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2019.01.010
State	Published - Mar 20 2019

Funding

We thank Alex Strongin from Sanford-Burnham-Prebys Discovery Institute for the ZIKV NS2B3 clone; Guo-li Ming and Hongjun Song from University of Pennsylvania for NS2B and NS3 clones; Amy Gladfelter from UNC for Septin clones; the Rockefeller University Bio-imaging Resource Center; Kevin Cannon at The University of North Carolina at Chapel Hill; Oswald Quehenberger, Aaron Armando, and Milda Simonaitis at the UCSD Lipidomics Core; and Alysson Muotri, Alexey Terskikh, Charles Rice, Margaret MacDonald, and Edward Holmes for discussions. H.L. is supported by a Druckenmiller Fellowship from the New York Stem Cell Foundation. The work was supported by NIH grant R01 NS106387 to J.G.G., A.V.T., and S.S. J.G.G. is an Investigator with the Howard Hughes Medical Institute. The Sohn Conference Foundation and the Leona M. and Harry B. Helmsley Charitable Trust are acknowledged for mass spectrometry instrumentation. We thank Alex Strongin from Sanford-Burnham-Prebys Discovery Institute for the ZIKV NS2B3 clone; Guo-li Ming and Hongjun Song from University of Pennsylvania for NS2B and NS3 clones; Amy Gladfelter from UNC for Septin clones; the Rockefeller University Bio-imaging Resource Center; Kevin Cannon at The University of North Carolina at Chapel Hill; Oswald Quehenberger, Aaron Armando, and Milda Simonaitis at the UCSD Lipidomics Core; and Alysson Muotri, Alexey Terskikh, Charles Rice, Margaret MacDonald, and Edward Holmes for discussions. H.L. is supported by a Druckenmiller Fellowship from the New York Stem Cell Foundation . The work was supported by NIH grant R01 NS106387 to J.G.G., A.V.T., and S.S. J.G.G. is an Investigator with the Howard Hughes Medical Institute . The Sohn Conference Foundation and the Leona M. and Harry B. Helmsley Charitable Trust are acknowledged for mass spectrometry instrumentation.

Keywords

Zika
activated caspase
cytokinesis
microcephaly
protease
septin

ASJC Scopus subject areas

General Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neuron.2019.01.010

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Li, H., Saucedo-Cuevas, L., Yuan, L., Ross, D., Johansen, A., Sands, D., Stanley, V., Guemez Gamboa, A. D., Gregor, A., Evans, T., Chen, S., Tan, L., Molina, H., Sheets, N., Shiryaev, S. A., Terskikh, A. V., Gladfelter, A. S., Shresta, S., Xu, Z., & Gleeson, J. G. (2019). Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors. Neuron, 101(6), 1089-1098.e4. https://doi.org/10.1016/j.neuron.2019.01.010

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title = "Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors",

abstract = "Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity. Video Abstract: Mechanisms by which Zika virus leads to microcephaly are poorly understood. Here, Li et al. demonstrate the Zika protease, required for viral replication, associates with host proteins and cleaves Septin-2, a protein required for neural cell division.",

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Li, H, Saucedo-Cuevas, L, Yuan, L, Ross, D, Johansen, A, Sands, D, Stanley, V, Guemez Gamboa, AD, Gregor, A, Evans, T, Chen, S, Tan, L, Molina, H, Sheets, N, Shiryaev, SA, Terskikh, AV, Gladfelter, AS, Shresta, S, Xu, Z & Gleeson, JG 2019, 'Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors', Neuron, vol. 101, no. 6, pp. 1089-1098.e4. https://doi.org/10.1016/j.neuron.2019.01.010

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T1 - Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors

AU - Li, Hongda

AU - Saucedo-Cuevas, Laura

AU - Yuan, Ling

AU - Ross, Danica

AU - Johansen, Anide

AU - Sands, Daniel

AU - Stanley, Valentina

AU - Guemez Gamboa, Alicia Dione

AU - Gregor, Anne

AU - Evans, Todd

AU - Chen, Shuibing

AU - Tan, Lei

AU - Molina, Henrik

AU - Sheets, Nicholas

AU - Shiryaev, Sergey A.

AU - Terskikh, Alexey V.

AU - Gladfelter, Amy S.

AU - Shresta, Sujan

AU - Xu, Zhiheng

AU - Gleeson, Joseph G.

PY - 2019/3/20

Y1 - 2019/3/20

N2 - Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity. Video Abstract: Mechanisms by which Zika virus leads to microcephaly are poorly understood. Here, Li et al. demonstrate the Zika protease, required for viral replication, associates with host proteins and cleaves Septin-2, a protein required for neural cell division.

AB - Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity. Video Abstract: Mechanisms by which Zika virus leads to microcephaly are poorly understood. Here, Li et al. demonstrate the Zika protease, required for viral replication, associates with host proteins and cleaves Septin-2, a protein required for neural cell division.

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KW - protease

KW - septin

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ER -

Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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