Letter | Published:

RNase III nucleases from diverse kingdoms serve as antiviral effectors

Nature volume 547, pages 114117 (06 July 2017) | Download Citation


In contrast to the DNA-based viruses in prokaryotes, the emergence of eukaryotes provided the necessary compartmentalization and membranous environment for RNA viruses to flourish, creating the need for an RNA-targeting antiviral system1,2. Present day eukaryotes employ at least two main defence strategies that emerged as a result of this viral shift, namely antiviral RNA interference and the interferon system2. Here we demonstrate that Drosha and related RNase III ribonucleases from all three domains of life also elicit a unique RNA-targeting antiviral activity. Systemic evolution of ligands by exponential enrichment of this class of proteins illustrates the recognition of unbranched RNA stem loops. Biochemical analyses reveal that, in this context, Drosha functions as an antiviral clamp, conferring steric hindrance on the RNA-dependent RNA polymerases of diverse positive-stranded RNA viruses. We present evidence for cytoplasmic translocation of RNase III nucleases in response to virus in diverse eukaryotes including plants, arthropods, fish, and mammals. These data implicate RNase III recognition of viral RNA as an antiviral defence that is independent of, and possibly predates, other known eukaryotic antiviral systems.

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We thank J. K. Lim and A. G. Pletnev for Langat virus reagents, B. Lee for Sendai virus reagents, R. W. Hardy for SINV reagents, B. R. Cullen for NoDice cells, K. K. Conzelmann for BSR-T7 cells, and B. Ramratnam for pEGFP–Drosha. Recombinant IFN-β was provided by the National Institute of Health’s Biodefense and Emerging Infections Research Resources Repository (HuIFN-β, NR-3080). This material is based upon work supported in part by the Burroughs Wellcome Fund, which provides support for both S.C. and B.R.T. S.C. is also supported by the National Institute of Allergy and Infectious Diseases (NIAID) (R01A1074951). J.P.L. is supported by the DIM Malinf, Conseil Regional d’Ile-de-France. L.C.A. is partly supported by the American Heart Association (15PRE24930012). A.E.S. is supported by National Science Foundation (MCB-1411836) and NIAID (R21AI117882). J.M. is supported by National Institute of General Medicine (F32 GM119235). B.R.T. is also supported by NIAID (R01AI110575).

Author information

Author notes

    • Lauren C. Aguado
    •  & Sonja Schmid

    These authors contributed equally to this work.


  1. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Lauren C. Aguado
    • , Sonja Schmid
    • , Maryline Panis
    • , Daniel Blanco-Melo
    •  & Benjamin R. tenOever
  2. Department of Cell Biology and Molecular Genetics, University of Maryland College Park, College Park, Maryland 20742, USA

    • Jared May
    •  & Anne E. Simon
  3. Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Leah R. Sabin
    •  & Sara Cherry
  4. Department of Pharmacology and Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Jaehee V. Shim
  5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • David Sachs
  6. Macrophages et Développement de l’Immunité, Institut Pasteur, CNRS UMR3738, 25–28 rue du Dr. Roux, 75724 Paris Cedex 15, France

    • Jean-Pierre Levraud


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L.C.A. and S.S. designed and conducted experiments. M.P. performed SELEX. J.M., L.C.A., and A.E.S. were responsible for plant data. L.S. and S.C. generated the Drosophila data. J.V.S. generated the RNaseIII−/− cells. J.P.L. and L.C.A. performed the zebrafish work. D.S. and D.B.M. were responsible for all bioinformatics. B.R.T., L.C.A., and S.S. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Benjamin R. tenOever.

Reviewer Information Nature thanks B. Cullen, L. Maraffini and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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