siRNA containing a unique 5-nucleotide motif acts as a quencher of IFI16-mediated innate immune response

Mol Immunol. 2019 Oct;114:330-340. doi: 10.1016/j.molimm.2019.08.007. Epub 2019 Aug 21.

Abstract

We previously reported that some small interfering RNA (siRNA) enhances DNA or DNA virus mediated-interferon (IFN)-λ1(a type III IFN) induction through the crosstalk between retinoic acid-inducible gene I (RIG-I) and interferon gamma-inducible protein 16 (IFI16) signalling pathway. Here we provide further evidence of a new role for siRNA. siRNA containing a 5-nucleotide (nt) motif sequence suppresses DNA-mediated not only type III IFNs, but also type I IFNs and inflammatory cytokines. We define that motif siRNA inhibits the induction when the motif is located at the 3' or 5'-terminus of siRNA. Using THP1-Lucia ISG cells with various DNA stimulants, we reveal that motif siRNA inhibits DNA or DNA virus but not RNA virus-mediated signalling. Motif siRNA specifically interrupts IFI16 but not cyclic GMP-AMP synthase (cGAS) binding to DNA and has 2.5-fold higher affinity to IFI16 than that of siRNA without the motif. We further confirm that motif siRNA potently suppresses HSV-1 virus-mediated IFNs and inflammatory cytokines, such as IFNL1, IFNB and TNFA, in human primary immature dendritic cells. Collectively, these findings may shed light on a novel function of siRNA with the unique 5-nt motif as a quencher of innate immunity and facilitate the development of potential therapeutics to regulate innate immune cascades.

Keywords: Immunosuppressive motif; Innate immunity; Interferon gamma-inducible protein 16 (IFI16); siRNA.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Cells, Cultured
  • Cytokines / immunology
  • DNA / immunology
  • Dendritic Cells / immunology
  • HEK293 Cells
  • HeLa Cells
  • Herpesvirus 1, Human / immunology
  • Humans
  • Immunity, Innate / immunology*
  • Interferon Type I / immunology
  • Nuclear Proteins / immunology*
  • Nucleotide Motifs / physiology*
  • Phosphoproteins / immunology*
  • RNA, Small Interfering / immunology*
  • Signal Transduction / immunology
  • THP-1 Cells

Substances

  • Cytokines
  • Interferon Type I
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • IFI16 protein, human
  • DNA