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

Arabinda Nayak | Dong Young Kim | Michael J Trnka | Craig H Kerr | Peter V Lidsky | David J Stanley | Brianna Monique Rivera | Kathy H Li | Alma L Burlingame | Eric Jan | Judith Frydman | John D Gross | Raul Andino
Cell host & microbe | 2018

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.

Pubmed ID: 30308158

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: P41 GM103481
  • Agency: NIH HHS, United States
    Id: S10 OD016229
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI127447
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NIGMS NIH HHS, United States
    Id: P50 GM082250
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI137471
  • Agency: NIAID NIH HHS, United States
    Id: P01 AI091575
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM078360

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