Structural basis for STAT2 suppression by flavivirus NS5 PMID: 32778820

ADC Targets in Oncology

2026-04-10

Structural basis for STAT2 suppression by flavivirus NS5

Nat Struct Mol Biol. 2020 Oct;27(10):875-885. doi: 10.1038/s41594-020-0472-y.

Boxiao Wang ^# ¹ , Stephanie Thurmond ^# ² ³ , Kang Zhou ^# ⁴ , Maria T Sánchez-Aparicio ^# ⁵ ⁶ , Jian Fang ¹ , Jiuwei Lu ¹ , Linfeng Gao ⁷ , Wendan Ren ¹ , Yanxiang Cui ⁴ , Ethan C Veit ⁶ , HeaJin Hong ¹ , Matthew J Evans ⁶ , Seán E O'Leary ¹ , Adolfo García-Sastre ⁵ ⁶ ⁸ ⁹ , Z Hong Zhou ¹⁰ ¹¹ , Rong Hai ¹² ¹³ , Jikui Song ¹⁴ ¹⁵

Affiliations

1. Department of Biochemistry, University of California, Riverside, CA, USA.
2. Department of Microbiology and Plant Pathology, University of California, Riverside, CA, USA.
3. Cell, Molecular and Developmental Biology Graduate Program, University of California, Riverside, CA, USA.
4. California NanoSystems Institute, University of California, Los Angeles, CA, USA.
5. GlobalHealth and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7. Environmental Toxicology Graduate Program, University of California, Riverside, CA, USA.
8. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
10. California NanoSystems Institute, University of California, Los Angeles, CA, USA. [email protected].
11. Departement of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA. [email protected].
12. Department of Microbiology and Plant Pathology, University of California, Riverside, CA, USA. [email protected].
13. Cell, Molecular and Developmental Biology Graduate Program, University of California, Riverside, CA, USA. [email protected].
14. Department of Biochemistry, University of California, Riverside, CA, USA. [email protected].
15. Environmental Toxicology Graduate Program, University of California, Riverside, CA, USA. [email protected].
# Contributed equally.

Abstract

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.