Structural basis for STAT2 suppression by flavivirus NS5

Boxiao Wang, Stephanie Thurmond, Kang Zhou, Maria T. Sánchez-Aparicio, Jian Fang, Jiuwei Lu, Linfeng Gao, Wendan Ren, Yanxiang Cui, Ethan C. Veit, Hea Jin Hong, Matthew J. Evans, Seán E. O’Leary, Adolfo García-Sastre, Z. Hong Zhou, Rong Hai, Jikui Song

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish
Pages (from-to)875-885
Number of pages11
JournalNature Structural and Molecular Biology
Issue number10
StatePublished - 1 Oct 2020


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