A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability

Cell Host Microbe. 2018 Oct 10;24(4):542-557.e9. doi: 10.1016/j.chom.2018.09.006.

Abstract

The dicistrovirus, Cricket paralysis virus (CrPV) encodes an RNA interference (RNAi) suppressor, 1A, which modulates viral virulence. Using the Drosophila model, we combined structural, biochemical, and virological approaches to elucidate the strategies by which CrPV-1A restricts RNAi immunity. The atomic resolution structure of CrPV-1A uncovered a flexible loop that interacts with Argonaute 2 (Ago-2), thereby inhibiting Ago-2 endonuclease-dependent immunity. Mutations disrupting Ago-2 binding attenuates viral pathogenesis in wild-type but not Ago-2-deficient flies. CrPV-1A also contains a BC-box motif that enables the virus to hijack a host Cul2-Rbx1-EloBC ubiquitin ligase complex, which promotes Ago-2 degradation and virus replication. Our study uncovers a viral-based dual regulatory program that restricts antiviral immunity by direct interaction with and modulation of host proteins. While the direct inhibition of Ago-2 activity provides an efficient mechanism to establish infection, the recruitment of a ubiquitin ligase complex enables CrPV-1A to amplify Ago-2 inactivation to restrict further antiviral RNAi immunity.

Keywords: Ago-2; Ago-2 degradation; CrPV; E3 ligase; RNAi; RNAi suppressor; antiviral immunity; insects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins / chemistry
  • Argonaute Proteins / metabolism*
  • Cell Line
  • Dicistroviridae / pathogenicity*
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / immunology*
  • Drosophila melanogaster / virology*
  • Humans
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Maps
  • RNA Interference / immunology*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism
  • Viral Proteins / chemistry
  • Viral Proteins / metabolism*
  • Virus Replication / immunology

Substances

  • AGO2 protein, Drosophila
  • Argonaute Proteins
  • Drosophila Proteins
  • Viral Proteins
  • Ubiquitin-Protein Ligases

Supplementary concepts

  • Cricket paralysis virus