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

Nat Immunol. 2014 Sep;15(9):839-45. doi: 10.1038/ni.2948. Epub 2014 Jul 27.


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.

Publication types

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

MeSH terms

  • Animals
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / immunology*
  • Diarrhea, Infantile / immunology*
  • Endoribonucleases / immunology*
  • Exosome Multienzyme Ribonuclease Complex*
  • Facies
  • Fetal Growth Retardation / immunology*
  • Gene Knockdown Techniques
  • Hair Diseases / immunology*
  • Humans
  • Immunity, Innate / immunology*
  • Interferon Type I / immunology
  • Mice, Inbred C57BL
  • Nuclear Proteins / immunology*
  • Protein-Serine-Threonine Kinases / immunology*
  • Proteins / immunology
  • RNA Helicases / immunology*
  • RNA-Binding Proteins / immunology*
  • Unfolded Protein Response / immunology*


  • Interferon Type I
  • Nuclear Proteins
  • Proteins
  • RNA-Binding Proteins
  • TTC7 protein, mouse
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Exosome Multienzyme Ribonuclease Complex
  • Ddx58 protein, mouse
  • MTREX protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • RNA Helicases
  • SKIV2L2 protein, mouse

Supplementary concepts

  • Trichohepatoenteric Syndrome