期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 27, 期 10, 页码 875-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-020-0472-y
关键词
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资金
- UC Cancer Research Coordinating Committee Faculty Seed Grant [CRR-20-634140]
- NIH [1R35GM119721, 1R21AI147057, R01GM071940, R21 AI133649, R00GM111858, 1S10RR23057, 1S10OD018111, U24GM116792]
- Trans fund of the State of California [AB2664]
- DHIPC (Dengue Human Immunology Project Consortium)
- NIAID funded program [U19AI118610]
- Burroughs Wellcome Fund
- China Scholarship Council
- UCLA
- NSF [DBI-1338135, DMR-1548924]
- office of science, office of basic energy sciences, of the US Department of Energy [DE-AC02-05CH11231]
Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy that viruses use to establish infections, yet the detailed mechanism remains elusive, owing to a lack of structural information about 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 interdomain 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 amino-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 conditions. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV. Cryo-EM, X-ray crystallography and mutational analyses reveal how Dengue and Zika virus protein NS5 suppresses STAT2 activity and interferon response in host cells.
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