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

• Published in: Nature immunology Vol. 15; no. 9; pp. 839 - 845
• Main Authors: Eckard, Sterling C, Rice, Gillian I, Fabre, Alexandre, Badens, Catherine, Gray, Elizabeth E, Hartley, Jane L, Crow, Yanick J, Stetson, Daniel B
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2014; Nature Publishing Group
• Subjects: 631/250; Animals; Biomedicine; Cellular signal transduction; DEAD Box Protein 58; DEAD-box RNA Helicases - immunology; Deoxyribonucleic acid; Diarrhea, Infantile - immunology; DNA; Endoribonucleases - immunology; Exosome Multienzyme Ribonuclease Complex; Facies; Fetal Growth Retardation - immunology; Gene Knockdown Techniques; Genetic aspects; Hair Diseases - immunology; Helicases; Humans; Immune system; Immunity, Innate - immunology; Immunology; Infectious Diseases; Interferon; Interferon Type I - immunology; Mice, Inbred C57BL; Natural immunity; Nuclear Proteins - immunology; Nucleic acids; Protein Serine-Threonine Kinases - immunology; Proteins - immunology; RNA Helicases - immunology; RNA-Binding Proteins - immunology; Sensors; Unfolded Protein Response - immunology; Virus activation
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2948

RIG-I-like receptors are activated by viral and other foreign RNAs. Stetson and colleagues show that the RNA exosome enzyme SKIV2L prevents RIG-I activation by endogenous RNAs generated by IRE-1 in stressed cells.
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.