SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition

Tan A. Nguyen, Blake R.C. Smith, Michelle D. Tate, Gabrielle T Belz, Marilou H. Barrios, Kirstin D. Elgass, Alexandra S. Weisman, Paul J. Baker, Simon Peter Preston, Lachlan W Whitehead, Alexandra L. Garnham, Rachel J. Lundie, Gordon K Smyth, Marc Pellegrini, Meredith O'Keeffe, Ian Peter Wicks, Seth L. Masters, Craig P. Hunter, Ken C Pang

Research output: Contribution to journalArticleResearchpeer-review

37 Citations (Scopus)


Double-stranded RNA (dsRNA) is a common by-product of viral infections and acts as a potent trigger of antiviral immunity. In the nematode C. elegans, sid-1 encodes a dsRNA transporter that is highly conserved throughout animal evolution, but the physiological role of SID-1 and its orthologs remains unclear. Here, we show that the mammalian SID-1 ortholog, SIDT2, is required to transport internalized extracellular dsRNA from endocytic compartments into the cytoplasm for immune activation. Sidt2-deficient mice exposed to extracellular dsRNA, encephalomyocarditis virus (EMCV), and herpes simplex virus 1 (HSV-1) show impaired production of antiviral cytokines and-in the case of EMCV and HSV-1-reduced survival. Thus, SIDT2 has retained the dsRNA transport activity of its C. elegans ortholog, and this transport is important for antiviral immunity. Extracellular double-stranded RNA is predominantly sensed by cytosolic RLRs after endocytic uptake, but how it enters the cytoplasm is unknown. Nguyen and colleagues demonstrate that the endo-lysosomal protein SIDT2 transports double-stranded RNA into the cytoplasm for RLR signaling and is required for survival after EMCV infection.

Original languageEnglish
Pages (from-to)498-509
Number of pages12
Issue number3
Publication statusPublished - 19 Sep 2017


  • Bystander immunity
  • Double-stranded RNA
  • EMCV
  • HSV
  • MAVS
  • SIDT2
  • Type I interferon
  • Virus infection

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