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Journal of General Virology header logo Journal of General Virology

Volume 106, Issue 1

Ubiquitin-like modifier-activating enzyme 1 interacts with Zika virus NS5 and promotes viral replication in the infected cell Open Access

Abstract

Translation errors, impaired folding or environmental stressors (e.g. infection) can all lead to an increase in the presence of misfolded proteins. These activate cellular responses to their removal, including intracellular protein degradation activities. Protein ubiquitylation is involved in two major degradation pathways, the ubiquitin-proteasome system and selective autophagy. In humans, the ubiquitin-like modifier-activating enzyme 1 (UBA1) is the primary E1 enzyme in the ubiquitin conjugation cascade. Viruses have evolved to exploit protein degradation pathways to complete their infection cycles. Zika virus (ZIKV) is an emerging orthoflavivirus causing serious neurologic disorders in neonates (congenital microcephaly) and adults (Guillain–Barré syndrome). Non-structural protein 5 (NS5), the largest and most conserved protein in the orthoflaviviruses, catalyses the synthesis and capping of new viral genomes. In addition to viral RNA replication in the cytoplasm, ZIKV NS5 is translocated into the nucleus to interfere with host antiviral responses. Here, we demonstrate that ZIKV NS5 co-immunoprecipitates with cellular UBA1. Immunofluorescence assays suggest that this interaction takes place primarily in the nucleus of an infected cell, although colocalization of both proteins is also detected in the cytosol. RNA interference-mediated depletion of UBA1 leads to reduced virus titres in the infected cells, while transient overexpression of UBA1 favours faster replication kinetics, with higher virus titres and protein levels detected. Moreover, UBA1-targeting drugs cause significant drops in virus infectivity. These results support a proviral role for UBA1 during ZIKV infection and encourage the potential use of inhibitors against this enzyme or its NS5-interacting epitopes as potential therapeutic targets.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): host–virus interactions , orthoflavivirus , RNA virus replication , RNA-dependent RNA polymerase , ubiquitin-proteasome system and Usutu virus
Funding
This study was supported by the:
  • Universidad de Castilla-La Mancha (Award 2024-INVGO-12348)
    • Principle Award Recipient: MaríaJosé Romero de Ávila
  • Universidad de Castilla-La Mancha (Award 2020-PREDUCLM-16723)
    • Principle Award Recipient: ImanolRodrigo
  • Universidad de Castilla-La Mancha (Award 2022-GRIN-34150)
    • Principle Award Recipient: ArmandoArias
  • Junta de Comunidades de Castilla-La Mancha (Award SBPLY/21/180501/000076)
    • Principle Award Recipient: ArmandoArias
  • Ministerio de Ciencia, Innovación y Universidades (Award CNS2022-135258)
    • Principle Award Recipient: ArmandoArias
  • Ministerio de Ciencia, Innovación y Universidades (Award BEAGAL18/00074)
    • Principle Award Recipient: ArmandoArias
  • Ministerio de Ciencia, Innovación y Universidades (Award PID2022-137974OB-I00)
    • Principle Award Recipient: ArmandoArias
  • Ministerio de Ciencia, Innovación y Universidades (Award PID2019-106068GB-I00)
    • Principle Award Recipient: ArmandoArias
© 2025 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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2025-01-08
2025-01-14
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Ubiquitin-like modifier-activating enzyme 1 interacts with Zika virus NS5 and promotes viral replication in the infected cell
J. Gen. Virol. 106, 002063 (2025); https://doi.org/10.1099/jgv.0.002063
/content/journal/jgv/10.1099/jgv.0.002063
/content/journal/jgv/10.1099/jgv.0.002063
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