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Identification of a critical role for ZIKV capsid α3 in virus assembly and its genetic interaction with M protein

Anastazia Jablunovsky1, Anoop Narayanan1, Joyce Jose1,2

  • 1Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.

Plos Neglected Tropical Diseases
|January 2, 2024
PubMed

Insights

Researchers identified a key interaction between Zika virus capsid (C) and membrane (M) proteins, crucial for virus assembly and production. This discovery offers new insights into flavivirus biogenesis and potential therapeutic targets.

Area of Science:

  • Virology
  • Molecular Biology
  • Structural Biology

Background:

  • Flaviviruses like Zika and dengue pose significant global health challenges, with limited treatment options.
  • Understanding flavivirus life cycle, particularly virion assembly and genome packaging, is crucial for developing effective interventions.
  • The function of the flavivirus capsid protein's (C) external α3 helix (C α3) in virus biogenesis remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of the C α3 helix in Zika virus (ZIKV) particle production.
  • To elucidate the molecular mechanisms underlying flavivirus assembly and identify potential protein-protein interactions involved.

Main Methods:

  • Alanine scanning mutagenesis of surface-exposed residues on the ZIKV C α3 helix.
  • In vitro assays to assess C protein dimerization and RNA binding.
  • Construction and characterization of infectious ZIKV cDNA clones with specific mutations.
  • Isolation and sequencing of revertant viruses to identify compensatory mutations.

Main Results:

  • A critical residue (CN67) in the ZIKV C α3 helix was identified as essential for virion production.
  • The CN67A mutation severely impaired ZIKV assembly and resulted in a highly attenuated viral phenotype.
  • A second-site mutation (MF37L) in the viral membrane (M) protein was found to genetically interact with the C protein mutation, restoring viral fitness.
  • Analogous mutations in dengue virus C and M proteins yielded similar results, suggesting conserved mechanisms in Aedes-transmitted flaviviruses.

Conclusions:

  • The study provides the first experimental evidence of a genetic interaction between the flavivirus C and M proteins.
  • This C-M protein interaction is critical for efficient virion assembly and budding in Aedes-transmitted flaviviruses.
  • The findings offer a mechanistic understanding of flavivirus biogenesis and highlight potential targets for antiviral strategies.

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