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Journal of General Virology header logo Journal of General Virology

Volume 106, Issue 3

Cytoplasmic retention of dengue virus capsid protein by metformin impairing nuclear transport Open Access

Abstract

Nuclear transport of proteins larger than 60 kDa occurs via energy-dependent active transport, whereas smaller proteins diffuse into the nucleus through nuclear pore complexes via passive nuclear transport. Although the dengue virus (DENV) replication cycle primarily takes place in the cytoplasm, the capsid protein and non-structural protein 5 (NS5) are imported into the nucleus through a nuclear localization sequence-dependent mechanism. However, given its small molecular weight (14 kDa), the DENV capsid protein may also enter the nucleus via passive diffusion. While some drugs primarily inhibit active nuclear transport, few are known to block passive diffusion. Notably, biguanides have been associated with inhibitory effects on passive nuclear transport. Since biguanides such as metformin (MET) exhibit anti-DENV properties, we investigated the effects of MET on the nuclear transport of DENV proteins. Our results suggest that MET induces changes in the nuclear membrane of Huh-7 cells and reduces capsid nuclear localization without affecting NS5 nuclear import. Furthermore, MET treatment did not alter capsid nuclear import in BHK-21 cells. Additionally, mimicking MET’s effects using a non-hydrolyzable ATP analogue increased capsid cytoplasmic retention and decreased DENV-2 replication. Finally, the inhibition of the classical active nuclear transport pathway did not block capsid nuclear transport, suggesting that DENV-2 capsid enters the nucleus in Huh-7 and Vero cells independently of this pathway.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): capsid protein , dengue virus (DENV) , metformin , nuclear passive transport and nuclear transport inhibition
Funding
This study was supported by the:
  • Conahcyt (Award A1-S-9005)
    • Principal Award Recipient: RosaM del Angel
  • Conahcyt (Award 302979)
    • Principal Award Recipient: RosaM del Angel
© 2025 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2025-03-20
2026-02-16

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/content/journal/jgv/10.1099/jgv.0.002089
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Cytoplasmic retention of dengue virus capsid protein by metformin impairing nuclear transport
J. Gen. Virol. 106, 002089 (2025); https://doi.org/10.1099/jgv.0.002089
/content/journal/jgv/10.1099/jgv.0.002089
/content/journal/jgv/10.1099/jgv.0.002089
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