4.6 Article

Flavivirus Capsid Proteins Inhibit the Interferon Response

Journal

VIRUSES-BASEL
Volume 14, Issue 5, Pages -

Publisher

MDPI
DOI: 10.3390/v14050968

Keywords

flaviviruses; global transcription; capsid protein; interferon response; TRIM25; Zika virus

Categories

Funding

  1. Frederick Banting & Charles Best Canada Graduate Doctoral Scholarship from the Canadian Institutes of Health Research (CIHR)
  2. CIHR [PJT-159442, PJT-148699, ZV1-149782]

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Flavivirus capsid proteins, including ZIKV capsid protein, can suppress the expression of IFN and IFN-stimulated genes. ZIKV capsid protein interacts with TRIM25 to prevent ubiquitination of RIG-I CARD domains, potentially attenuating antiviral signaling pathways at early stages of infection.
Zika virus (ZIKV) establishes persistent infections in multiple human tissues, a phenomenon that likely plays a role in its ability to cause congenital birth defects and neurological disease. Multiple nonstructural proteins encoded by ZIKV, in particular NS5, are known to suppress the interferon (IFN) response by attacking different steps in this critical antiviral pathway. Less well known are the potential roles of structural proteins in affecting the host immune response during ZIKV infection. Capsid proteins of flaviviruses are of particular interest because a pool of these viral proteins is targeted to the nuclei during infection and, as such, they have the potential to affect host cell gene expression. In this study, RNA-seq analyses revealed that capsid proteins from six different flaviviruses suppress expression of type I IFN and IFN-stimulated genes. Subsequent interactome and in vitro ubiquitination assays showed that ZIKV capsid protein binds to and prevents activating ubiquitination of RIG-I CARD domains by TRIM25, a host factor that is important for the induction arm of the IFN response. The other flavivirus capsid proteins also interacted with TRIM25, suggesting that these viral proteins may attenuate antiviral signaling pathways at very early stages of infection, potentially even before nonstructural proteins are produced.

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