Invading viral DNA triggers dsRNA synthesis by RNA polymerase II to activate antiviral RNA interference in Drosophila

Cell Rep. 2022 Jun 21;39(12):110976. doi: 10.1016/j.celrep.2022.110976.

Abstract

dsRNA sensing triggers antiviral responses against RNA and DNA viruses in diverse eukaryotes. In Drosophila, Invertebrate iridescent virus 6 (IIV-6), a large DNA virus, triggers production of small interfering RNAs (siRNAs) by the dsRNA sensor Dicer-2. Here, we show that host RNA polymerase II (RNAPII) bidirectionally transcribes specific AT-rich regions of the IIV-6 DNA genome to generate dsRNA. Both replicative and naked IIV-6 genomes trigger production of dsRNA in Drosophila cells, implying direct sensing of invading DNA. Loquacious-PD, a Dicer-2 co-factor essential for the biogenesis of endogenous siRNAs, is dispensable for processing of IIV-6-derived dsRNAs, which suggests that they are distinct. Consistent with this finding, inhibition of the RNAPII co-factor P-TEFb affects the synthesis of endogenous, but not virus-derived, dsRNA. Altogether, our results suggest that a non-canonical RNAPII complex recognizes invading viral DNA to synthesize virus-derived dsRNA, which activates the antiviral siRNA pathway in Drosophila.

Keywords: CP: Immunology; DNA sensing; antiviral RNAi; dsRNA; invertebrate immunity.

MeSH terms

  • Animals
  • Antiviral Agents
  • DNA Viruses / genetics
  • DNA, Viral*
  • Drosophila* / metabolism
  • Iridovirus
  • RNA Interference
  • RNA Polymerase II / metabolism
  • RNA, Double-Stranded / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Viral / metabolism

Substances

  • Antiviral Agents
  • DNA, Viral
  • RNA, Double-Stranded
  • RNA, Small Interfering
  • RNA, Viral
  • RNA Polymerase II

Supplementary concepts

  • Invertebrate iridescent virus 6