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Structural basis for STAT2 suppression by flavivirus NS5

Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy viruses use to establish infections, yet the detailed mechanism remains elusive due to lack of structural information of the viral-cellular complex involved. Here, we report the cryo-EM and crystal structures of...

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Autores principales: Wang, Boxiao, Thurmond, Stephanie, Zhou, Kang, Sánchez-Aparicio, Maria T., Fang, Jian, Lu, Jiuwei, Gao, Linfeng, Ren, Wendan, Cui, Yanxiang, Veit, Ethan C, Hong, HeaJin, Evans, Matthew J, O’Leary, Seán E., García-Sastre, Adolfo, Zhou, Z. Hong, Hai, Rong, Song, Jikui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554153/
https://www.ncbi.nlm.nih.gov/pubmed/32778820
http://dx.doi.org/10.1038/s41594-020-0472-y
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author Wang, Boxiao
Thurmond, Stephanie
Zhou, Kang
Sánchez-Aparicio, Maria T.
Fang, Jian
Lu, Jiuwei
Gao, Linfeng
Ren, Wendan
Cui, Yanxiang
Veit, Ethan C
Hong, HeaJin
Evans, Matthew J
O’Leary, Seán E.
García-Sastre, Adolfo
Zhou, Z. Hong
Hai, Rong
Song, Jikui
author_facet Wang, Boxiao
Thurmond, Stephanie
Zhou, Kang
Sánchez-Aparicio, Maria T.
Fang, Jian
Lu, Jiuwei
Gao, Linfeng
Ren, Wendan
Cui, Yanxiang
Veit, Ethan C
Hong, HeaJin
Evans, Matthew J
O’Leary, Seán E.
García-Sastre, Adolfo
Zhou, Z. Hong
Hai, Rong
Song, Jikui
author_sort Wang, Boxiao
collection PubMed
description Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy viruses use to establish infections, yet the detailed mechanism remains elusive due to lack of structural information of the viral-cellular complex involved. Here, we report the cryo-EM and crystal structures of human STAT2 (hSTAT2) in complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revealing two-pronged interactions between NS5 and hSTAT2. First, the NS5 methyltransferase and RNA-dependent RNA polymerase (RdRP) domains form a conserved inter-domain cleft harboring the coiled-coil domain of hSTAT2, thus preventing association of hSTAT2 with interferon regulatory factor 9. Second, the NS5 RdRP domain also binds the N-terminal domain of hSTAT2. Disruption of these ZIKV NS5–hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppression, and viral infection under interferon-competent condition. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV.
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spelling pubmed-75541532021-02-10 Structural basis for STAT2 suppression by flavivirus NS5 Wang, Boxiao Thurmond, Stephanie Zhou, Kang Sánchez-Aparicio, Maria T. Fang, Jian Lu, Jiuwei Gao, Linfeng Ren, Wendan Cui, Yanxiang Veit, Ethan C Hong, HeaJin Evans, Matthew J O’Leary, Seán E. García-Sastre, Adolfo Zhou, Z. Hong Hai, Rong Song, Jikui Nat Struct Mol Biol Article Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy viruses use to establish infections, yet the detailed mechanism remains elusive due to lack of structural information of the viral-cellular complex involved. Here, we report the cryo-EM and crystal structures of human STAT2 (hSTAT2) in complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revealing two-pronged interactions between NS5 and hSTAT2. First, the NS5 methyltransferase and RNA-dependent RNA polymerase (RdRP) domains form a conserved inter-domain cleft harboring the coiled-coil domain of hSTAT2, thus preventing association of hSTAT2 with interferon regulatory factor 9. Second, the NS5 RdRP domain also binds the N-terminal domain of hSTAT2. Disruption of these ZIKV NS5–hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppression, and viral infection under interferon-competent condition. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV. 2020-08-10 2020-10 /pmc/articles/PMC7554153/ /pubmed/32778820 http://dx.doi.org/10.1038/s41594-020-0472-y Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wang, Boxiao
Thurmond, Stephanie
Zhou, Kang
Sánchez-Aparicio, Maria T.
Fang, Jian
Lu, Jiuwei
Gao, Linfeng
Ren, Wendan
Cui, Yanxiang
Veit, Ethan C
Hong, HeaJin
Evans, Matthew J
O’Leary, Seán E.
García-Sastre, Adolfo
Zhou, Z. Hong
Hai, Rong
Song, Jikui
Structural basis for STAT2 suppression by flavivirus NS5
title Structural basis for STAT2 suppression by flavivirus NS5
title_full Structural basis for STAT2 suppression by flavivirus NS5
title_fullStr Structural basis for STAT2 suppression by flavivirus NS5
title_full_unstemmed Structural basis for STAT2 suppression by flavivirus NS5
title_short Structural basis for STAT2 suppression by flavivirus NS5
title_sort structural basis for stat2 suppression by flavivirus ns5
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554153/
https://www.ncbi.nlm.nih.gov/pubmed/32778820
http://dx.doi.org/10.1038/s41594-020-0472-y
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