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

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

Author information

1
Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
2
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
3
1] UMR_S 910, Inserm-Faculte´ de Medecine, Aix-Marseille Universite, Marseille, France. [2] AP-HM, Service de Pediatrie Multidisciplinaire, Hopital d'Enfants de la Timone, Marseille, France.
4
1] UMR_S 910, Inserm-Faculte´ de Medecine, Aix-Marseille Universite, Marseille, France. [2] AP-HM, Laboratoire de Genetique Moleculaire, Hopital d'Enfants de la Timone, Marseille, France.
5
Liver Unit, Birmingham Children's Hospital, Birmingham, UK.

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.

PMID:
25064072
PMCID:
PMC4139417
DOI:
10.1038/ni.2948
[Indexed for MEDLINE]
Free PMC Article

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