Pestivirus Npro directly interacts with interferon regulatory factor 3 monomer and dimer

Keerthi Gottipati, Luis Marcelo F Holthauzen, Nicolas Ruggli, Kyung Choi

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Interferon regulatory factor 3 (IRF3) is a transcription factor involved in the activation of type I alpha/beta interferon (IFN-α/β) in response to viral infection. Upon viral infection, the IRF3 monomer is activated into a phosphorylated dimer, which induces the transcription of interferon genes in the nucleus. Viruses have evolved several ways to target IRF3 in order to subvert the innate immune response. Pestiviruses, such as classical swine fever virus (CSFV), target IRF3 for ubiquitination and subsequent proteasomal degradation. This is mediated by the viral protein Npro that interacts with IRF3, but the molecular details for this interaction are largely unknown. We used recombinant Npro and IRF3 proteins and show that Npro interacts with IRF3 directly without additional proteins and forms a soluble 1:1 complex. The full-length IRF3 but not merely either of the individual domains is required for this interaction. The interaction between Npro and IRF3 is not dependent on the activation state of IRF3, since Npro binds to a constitutively active form of IRF3 in the presence of its transcriptional coactivator, CREB-binding protein (CBP). The results indicate that the Npro-binding site on IRF3 encompasses a region that is unperturbed by the phosphorylation and subsequent activation of IRF3 and thus excludes the dimer interface and CBP-binding site.

    Original languageEnglish (US)
    Pages (from-to)7740-7747
    Number of pages8
    JournalJournal of Virology
    Volume90
    Issue number17
    DOIs
    StatePublished - 2016

    Fingerprint

    Pestivirus
    Interferon Regulatory Factor-3
    CREB-Binding Protein
    Virus Diseases
    interferon regulatory factor-3
    binding proteins
    binding sites
    Binding Sites
    Classical swine fever virus
    interferon-beta
    Interferon Type I
    Interferon-beta
    Ubiquitination
    viral proteins
    protein binding
    Viral Proteins
    interferons
    Innate Immunity

    ASJC Scopus subject areas

    • Immunology
    • Medicine(all)
    • Virology

    Cite this

    Pestivirus Npro directly interacts with interferon regulatory factor 3 monomer and dimer. / Gottipati, Keerthi; Holthauzen, Luis Marcelo F; Ruggli, Nicolas; Choi, Kyung.

    In: Journal of Virology, Vol. 90, No. 17, 2016, p. 7740-7747.

    Research output: Contribution to journalArticle

    Gottipati, Keerthi ; Holthauzen, Luis Marcelo F ; Ruggli, Nicolas ; Choi, Kyung. / Pestivirus Npro directly interacts with interferon regulatory factor 3 monomer and dimer. In: Journal of Virology. 2016 ; Vol. 90, No. 17. pp. 7740-7747.
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    abstract = "Interferon regulatory factor 3 (IRF3) is a transcription factor involved in the activation of type I alpha/beta interferon (IFN-α/β) in response to viral infection. Upon viral infection, the IRF3 monomer is activated into a phosphorylated dimer, which induces the transcription of interferon genes in the nucleus. Viruses have evolved several ways to target IRF3 in order to subvert the innate immune response. Pestiviruses, such as classical swine fever virus (CSFV), target IRF3 for ubiquitination and subsequent proteasomal degradation. This is mediated by the viral protein Npro that interacts with IRF3, but the molecular details for this interaction are largely unknown. We used recombinant Npro and IRF3 proteins and show that Npro interacts with IRF3 directly without additional proteins and forms a soluble 1:1 complex. The full-length IRF3 but not merely either of the individual domains is required for this interaction. The interaction between Npro and IRF3 is not dependent on the activation state of IRF3, since Npro binds to a constitutively active form of IRF3 in the presence of its transcriptional coactivator, CREB-binding protein (CBP). The results indicate that the Npro-binding site on IRF3 encompasses a region that is unperturbed by the phosphorylation and subsequent activation of IRF3 and thus excludes the dimer interface and CBP-binding site.",
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