SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition

Publication date: Available online 12 September 2017
Source:Immunity
Author(s): 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 P. Preston, Lachlan Whitehead, Alexandra Garnham, Rachel J. Lundie, Gordon K. Smyth, Marc Pellegrini, Meredith O'Keeffe, Ian P. Wicks, Seth L. Masters, Craig P. Hunter, Ken C. Pang
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.

Graphical abstract

Teaser

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.


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