2. Academic Validation
  3. Structural basis for STAT2 suppression by flavivirus NS5

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

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.
PMID: 32778820 DOI: 10.1038/s41594-020-0472-y
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.

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