Article | Published:

The SKIV2L RNA exosome limits activation of the RIG-I-like receptors

Nature Immunology volume 15, pages 839845 (2014) | Download Citation

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Abstract

Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.

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Acknowledgements

We thank M. Gale, Jr. (University of Washington) for Mavs−/− mice, and members of the Stetson laboratory for discussions. Supported by the National Institute of Allergy and Infectious Disease (AI084914 to D.B.S.), the Nuclease Immune Mediated Brain and Lupus-like conditions (NIMBL) project of the European Union Seventh Framework Programme 2007-2013 (241779 to Y.J.C. and D.B.S.), the Lupus Research Institute (D.B.S.), the Cancer Research Institute (E.E.G.) and the Rita Allen Foundation (D.B.S.).

Author information

Affiliations

  1. Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.

    • Sterling C Eckard
    • , Elizabeth E Gray
    •  & Daniel B Stetson
  2. Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.

    • Gillian I Rice
    •  & Yanick J Crow
  3. UMR_S 910, Inserm-Faculte´ de Medecine, Aix-Marseille Universite, Marseille, France.

    • Alexandre Fabre
    •  & Catherine Badens
  4. AP-HM, Service de Pediatrie Multidisciplinaire, Hopital d'Enfants de la Timone, Marseille, France.

    • Alexandre Fabre
  5. AP-HM, Laboratoire de Genetique Moleculaire, Hopital d'Enfants de la Timone, Marseille, France.

    • Catherine Badens
  6. Liver Unit, Birmingham Children's Hospital, Birmingham, UK.

    • Jane L Hartley

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Contributions

S.C.E. did all experiments with mouse cells; G.I.R. and Y.J.C. did the ISG analysis of human cells and helped write the manuscript; A.F., C.B. and J.L.H. obtained peripheral blood samples from patients with THES and control subjects, provided intellectual input and insights into human THES and helped write the manuscript; E.E.G. developed the Lenti-CRISPR system; and S.C.E. and D.B.S. designed the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel B Stetson.

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DOI

https://doi.org/10.1038/ni.2948

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